The GJB2 NM_004004.6:c.35del (NP_003995.2:p.(Gly12ValfsTer2)) frameshift variant has previously been reported in somatic cancers (COSMIC; COSV101241530, n = 1 time). Based on available guidelines, this variant is considered to be Benign. This variant is considered to be Pathogenic by the VCEP (ClinGen Hearing Loss Variant Curation Expert Panel; ClinVar ID 17004).
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.GJB2 encodes connexin 26, a member of the gap junction protein family. Connexins assemble into hexameric channels in the plasma membrane that regulate the passage of ions and small molecules between cells and, when joined between adjacent cells, form intercellular gap junction channels that allow direct cell-to-cell communication. Mutations in this gene are responsible for up to 50% of pre-lingual, recessive deafness. No established role in cancer is described.
The recorded framework is ClinGen GJB2 VCEP v2.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met, very strong: the exon-2 frameshift truncates GJB2 at residue 13 instead of the 227-residue reference protein.
Not applicable: the Hearing Loss VCEP explicitly excludes PP5 from use.
Met: all-comers gnomAD v4.1 AF 0.00704997 (0.70500%) exceeds the VCEP autosomal-recessive BA1 threshold of 0.005 (0.5%).
Met at strong: all-comers gnomAD v4.1 AF 0.00704997 (0.70500%) exceeds the VCEP autosomal-recessive BS1 strong threshold of 0.003 (0.3%).
Benign: BA1 stand-alone satisfies the benign rule; PVS1 very strong plus PP5 supporting does not satisfy a pathogenic combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 11,375 / 1,613,482 alleles. Recorded AF 0.00704997. Recorded homozygote count 38.
This variant is present in gnomAD v2.1 (AF= 0.00618819; MAF= 0.61882%, 1737/280696 alleles, homozygotes = 10) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00957755; MAF= 0.95775%, 1217/127068 alleles, homozygotes = 4); grpmax FAF= 0.0109023.
This variant is present in gnomAD-Canada v1.0 (AF= 0.006893931169254153, 127/18422 alleles, homozygotes = 1).
Recorded SpliceAI maximum delta score: 0.056. Refer to the recorded PP3/BP4 rationale for interpretation.
93 Pathogenic · 1 pathogenic · 1 Likely pathogenic. ClinVar API review status: reviewed by expert panel.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV101241530, n = 1 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under ClinGen GJB2 VCEP v2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 2 not met · 10 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No confirmed or assumed de novo occurrence is documented for PS2 or PM6.
Segregation is reported for c.35delG/p.(Gly12Valfs*2), but the affected-relative count needed for PP1 strength assignment is not provided.
No qualifying non-segregation with phenotype and diagnostic audiometric evidence is documented for BS4.
Only PS4, PP4, PP5, BP5, and BP6 were adjudicated.
PS4 remains not assessed because no verifiable case-control counts, odds ratio, confidence interval, or matched-ancestry control frequency were available.
PP4 remains not assessed because patient-specific phenotype information and the referenced VCEP Table 7 specifications were unavailable.
PP5 and BP6 are explicitly not applicable in this VCEP; BP5 is not applicable because the VCEP excludes it for autosomal-recessive disease.
All three requested computational-evidence criteria are not applicable from their VCEP-defined scopes: the variant is a coding frameshift, not a missense, splice-site, or silent variant.
The available SpliceAI result was not counted because the governing VCEP rules name MaxEntScan for the applicable splice-prediction paths, and BP4 is not applicable to a frameshift.
Population evidence supports BA1 stand-alone and BS1 strong because the all-comers gnomAD allele frequency is above both VCEP thresholds; PM2 is not met because the frequency is far above the VCEP rarity cutoff; BS2 remains unassessed because aggregate homozygote counts do not establish unaffected controls or the required trans genotype.
No criteria match.
NM_004004.6:c.35del is a frameshift in the coding portion of exon 2 of the MANE Select GJB2 transcript, producing NP_003995.2:p.(Gly12ValfsTer2) (p.G12Vfs*2), with a predicted protein of 13 residues versus 227 residues for the reference protein. The VCEP establishes GJB2 loss of function as a disease mechanism and defines a null variant in such a gene as PVS1 at very strong strength. No VCEP-named downgrade is supported by the available evidence: this is not a splice-consensus variant, extreme 3-prime variant, stop-loss variant, or an in-frame change, and the truncation occurs near the beginning of the coding sequence.
Null variant in a gene with established LOF as a disease mechanism; see PVS1_Strong, PVS1_Moderate, PVS1_Supporting for reduced evidence applications.
Expert panel ClinGen Hearing Loss Variant Curation Expert Panel classified as Pathogenic.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The Hearing Loss VCEP specifies BA1 at stand-alone strength when MAF is ≥0.005 (0.5%) for autosomal recessive disease. GJB2 is autosomal recessive. The variant's all-comers gnomAD v2.1 frequency is AF 0.00618819 (0.61882%; 1737/280696 alleles; 10 homozygotes), and gnomAD v4.1 frequency is AF 0.00704997 (0.70500%; 11375/1613482 alleles; 38 homozygotes). Both exceed the VCEP threshold, so BA1 is met. The VCEP does not specify a non-cancer or exome-only source for this criterion; therefore the default all-comers totals are used.
MAF of ≥0.005 (0.5%) for autosomal recessive; MAF of ≥0.001 (0.1%) for autosomal dominant.
The Hearing Loss VCEP specifies BS1 at strong strength when MAF is ≥0.003 (0.3%) for autosomal recessive disease, provided there is no conflicting evidence. GJB2 is autosomal recessive. The all-comers gnomAD v4.1 AF is 0.00704997 (0.70500%), and gnomAD v2.1 AF is 0.00618819 (0.61882%); both exceed 0.003. No population-frequency evidence in the reviewed bundle conflicts with the benign frequency interpretation. The VCEP does not specify a non-cancer or exome-only source for this criterion; therefore the default all-comers totals are used.
MAF of ≥0.003 (0.3%) for autosomal recessive; MAF of ≥0.0002 (0.02%) for autosomal dominant. Likely benign, provided there is no conflicting evidence.
The Hearing Loss VCEP specifies PM2 at supporting strength for an autosomal-recessive variant absent or present at ≤0.00007 (0.007%) in population databases. GJB2 is autosomal recessive. The all-comers gnomAD v2.1 AF is 0.00618819 (0.61882%) and the all-comers gnomAD v4.1 AF is 0.00704997 (0.70500%), both far above 0.00007; PM2 is therefore not met. The VCEP does not specify a non-cancer or exome-only source for this criterion; therefore the default all-comers totals are used.
Absent/Rare in population databases (absent or ≤0.00007 (0.007%) for autosomal recessive, ≤0.00002 (0.002%) for autosomal dominant).
The VCEP permits PM3_Supporting for a homozygous variant only when the variant meets PM2_Supporting, defined here as an autosomal-recessive allele absent or present at no more than 0.00007 (0.007%). The case includes a literature report of homozygous c.35delG/p.(Gly12Valfs*2) in affected probands, but the observed gnomAD v4.1 allele frequency for this normalized c.35del variant is 0.00704997 (0.705%), with 38 homozygotes, far above the VCEP PM2_Supporting threshold; no qualifying trans observations with a pathogenic variant are documented. Therefore PM3 is not met under the VCEP rule.
0.5 points awarded from tables 7a and 7b Examples: Two variants that meet PM2_Supporting detected in trans; OR a homozygous variant meeting PM2_Supporting. ... Absent/Rare in population databases (absent or ≤0.00007 (0.007%) for autosomal recessive, ≤0.00002 (0.002%) for autosomal dominant).
The available evidence does not document a de novo occurrence. The reported GJB2 c.35delG/p.(Gly12Valfs*2) observations are homozygous or inherited family observations, and there is no documented confirmation of both maternity and paternity for an affected proband. Therefore, the VCEP point-based PS2 rule cannot be evaluated.
4 points per tables 5a and 5b: Examples: 2 proven de novo occurrences; OR 1 proven + 2 assumed de novo occurrences; OR 4 assumed de novo occurrences.
The VCEP permits PS3_Moderate for GJB2 electrical-coupling or dye-transfer assays only when the variant shows a deleterious result against both an appropriate negative control and wild-type comparator. The available literature record for PMID:12176036 describes functional analysis of six GJB2 missense mutations and separately identifies common 35delG, but does not provide a variant-specific electrical-coupling or dye-transfer result for c.35del (35delG). The other reviewed exact-variant literature includes genotyping, clinical, or segregation information rather than a qualifying GJB2 functional assay. Therefore, PS3 cannot be evaluated from the available evidence and is not_assessed.
Validated functional studies show a deleterious effect (predefined list): GJB2: electrical coupling assays, dye transfer assays → PS3_Moderate * Dye Transfer Assays: Expect results that compare the fluorescence of a variant-transfected cell to both a negative control (or H2O injected control) and a wildtype-transfected cell. PS3_Moderate would be applied if the variant results in no dye transfer or significantly different dye transfer when compared to the wildtype. * Electrical Coupling Assays: Expect results comparing the current of the variant-transfected cells to both a negative control (i.e. H2O injected control) and a wildtype-transfected cell. PS3_Moderate would be applied if the variant results in significantly different current compared to the wildtype, and the current is comparable to background levels/negative control.
The VCEP PS4 rule requires Fisher Exact or Chi-Squared analysis showing a statistical increase in cases over controls, or, for an autosomal-dominant disease, at least 2/6/15 probands with PM2_Supporting. GJB2-related disease in this case is autosomal recessive, so the proband-count alternatives do not apply. The literature_pass.json packet has no paper in ai_classified_papers labeled PS4; its PS4 index lists papers, but the available paper extracts do not provide a case/control 2x2 table, an odds ratio, a confidence interval, or matched-ancestry control frequency for NM_004004.6:c.35del/c.35delG. The extracted studies report affected families or assay/population-panel observations without sufficient case-control counts. Therefore the VCEP case-control requirement cannot be evaluated and PS4 is not assessed.
Fisher Exact or Chi-Squared analysis shows statistical increase in cases over controls, OR Autosomal dominant: ≥15 probands with variant, and variant meets PM2_Supporting.
The available evidence does not document an assumed de novo occurrence. The reported observations are familial and/or homozygous, with no affected proband described as carrying the variant without parental origin confirmation. The VCEP directs PM6 to the PS2 rule, so no PM6 strength can be assigned.
See PS2 above
A segregation study reports homozygous GJB2 c.35delG/p.(Gly12Valfs*2) in two Pakistani families and states that the variant segregated with hearing loss. However, it does not enumerate the number of affected relatives carrying the variant for the reported families. Because the VCEP requires one, two, or three affected relatives for supporting, moderate, or strong evidence in recessive disease, the available evidence cannot be assigned a PP1 strength.
Segregation in three affected relatives for recessive and five affected relatives for dominant. Segregation in two affected relatives for recessive and 4 affected relatives for dominant. Segregation in one affected relative for recessive and two affected relatives for dominant.
The VCEP PP4 rule requires that the patient's phenotype be highly specific for the gene or a fully sequenced gene set and directs the evaluator to Table 7. The case materials provide no patient-specific phenotype or family-history description sufficient to compare with Table 7, and vcep_materials.json reports no domain tables. A general association of GJB2 with hearing loss cannot substitute for the required patient-specific, highly specific phenotype assessment.
Patient's phenotype highly specific for gene or fully sequenced gene set (see specifications in Table 7).
The VCEP requires observation of the variant biallelic with a known pathogenic variant in controls, inconsistent with disease penetrance, for recessive BS2. gnomAD reports 10 homozygotes in v2.1 and 38 homozygotes in v4.1, but the available records do not establish that these are unaffected controls or document a known pathogenic allele in trans. Population homozygote counts alone therefore cannot evaluate the VCEP rule.
The VCEP permits BS3_Supporting for GJB2 electrical-coupling or dye-transfer assays only when variant function is comparable to wild type against the specified negative control. No such variant-specific benign functional result for c.35del is available. PMID:12176036 concerns functional analysis of six missense mutations and does not report a c.35del-specific electrical-coupling or dye-transfer result; therefore BS3 cannot be evaluated and is not_assessed.
Functional study shows no deleterious effect (predefined list). * Recommend that functional evidence is not used as strong evidence, due to the absence of well-established functional studies for hearing loss genes. * Guidance on functional evidence at supporting level is as follows (see functional spreadsheets attached): * GJB2: electrical coupling assays, dye transfer assays → BS3_Supporting * Dye Transfer Assays: Expect results that compare the fluorescence of a variant-transfected cell to both a negative control (or H2O injected control) and a wildtype-transfected cell. BS2_Supporting can be applied if the variant results in dye transfer comparable to the wildtype. * Electrical Coupling Assays: Expect results comparing the current of the variant-transfected cells to both a negative control (or H2O injected control) and a wildtype-transfected cell. BS2_Supporting would be applied if the variant results in a current comparable to the wildtype. * SLC26A4: Radio isotope and fluorescence assays → BS3_Supporting * Radio Isotope Assays: BS3_Supporting would be applied if the variant results in iodide efflux levels comparable to the wildtype. * Fluorescence assay: BS3_Supporting would be applied if the variant results in fluorescence comparable to the wildtype * COCH: Localization, secretion, and dimerization studies performed using immunofluorescence and Western blotting techniques → BS3_Supporting * Localization: BS3_Supporting would be applied if the variant results in extracellular deposits comparable to the wildtype. * Secretion: BS3_Supporting would be applied if the variant results in secretion comparable to the wildtype. * Dimerization: In a non-reducing environment, wildtype cochlin migrate quickly and appear smaller than in the reduced state because the structure is maintained by disulfide bonds. BS3_Supporting would be applied if the variant results in molecular weight and size comparable to the wildtype. * If not listed above, OK to use BS3_Supporting for other genes/functional analyses if * The assay has been validated by a known pathogenic and benign variant AND * There is plausible reason that the function the assay is testing relates to the phenotype AND * The assay conditions are likely to mimic the physiological environment.
The available evidence does not document non-segregation. The family reports describe segregation with hearing loss or inherited/homozygous observations, but they do not provide a phenotype-positive/genotype-negative or genotype-positive/phenotype-negative relative meeting the VCEP requirements for confident non-segregation. No qualifying diagnostic audiometric evidence for an unaffected carrier is provided.
Non-segregation with disease. * Phenotype+/genotype- * Strong evidence for benign. * Be cautious when using this as the possibility for phenocopy is high. The hearing loss phenotype should be consistent within the family to consider it a non-segregation, though intra-familial variability has been reported. Factors to consider are: * Age of onset (ie. congenital/early childhood vs. adult onset). * Hearing loss prevalence increases significantly with age. A congenital hearing loss in a child and a late onset hearing loss in a grandparent would not be a consistent phenotype. * Severity (ie - mild vs. profound). * Minor differences may exist among family members. * Keep in mind that progression in older individuals may account for a discrepancy between individuals. * Sex -based differences (infertility, genes on X chromosomes) * Audiogram shape. * May not be completely consistent among family members even with same etiology. * Genotype+/phenotype- * Confounding variables to applying this rule: Age-related/sex-related penetrance, variable expressivity, etc. * If the gene is associated with later onset and individual with the non-segregation is beyond the expected age that the hearing loss would occur, consider applying BS4_Supporting * Recommend only using for fully penetrant genes (typically genes associated with AR hearing loss). * Must be confident that patient is truly unaffected and a hearing loss is not missed or subclinical. Be cautious if only phenotyping was newborn hearing screening. Diagnostic audiometric testing (auditory brainstem response (ABR) or audiogram should be required). * Any evidence for reduced penetrance, do not use BS4
The VCEP BP2 rule requires the variant to be observed in trans with a dominant variant or in cis with a pathogenic variant, with caution for genes having dominant and recessive hearing-loss mechanisms. The available evidence documents homozygous observations but does not establish cis or trans phase with a pathogenic or dominant variant, so BP2 cannot be evaluated.
Observed in trans with a dominant variant/observed in cis with a pathogenic variant (use with caution). Use with caution. For genes that are associated with both dominant and recessive hearing loss, consider whether an earlier onset/more severe phenotype could be present if variant is identified in trans with a dominant variant.
PS1 is not applicable because the case variant is NM_004004.6:c.35del, normalized as NP_003995.2:p.(Gly12ValfsTer2), a frameshift variant. The VCEP PS1 rule applies to the same amino acid change as an established pathogenic variant or to splice variants at the same nucleotide with similar impact; this frameshift is neither a same-amino-acid missense change nor a splice variant at the same nucleotide.
Same amino acid change as an established pathogenic variant; OR splice variants at same nucleotide and with similar impact prediction as previously reported pathogenic variant. * Established variant must meet criteria for pathogenicity by the HL specifications * Can also use PS1 for splice variants located in the splice consensus sequence, at the same nucleotide position as a previously reported pathogenic variant * Example: c.105+1G>C is known to be pathogenic, can use PS1 for c.105+1G>T * No additional hearing loss specifications for missense variants. Follow recommendations as outlined in Richard 2015 and/or the Sequence Variant Interpretation working group within ClinGen. * Caveat (from ACMG/AMP guidelines): Assess the possibility that the variant may act directly through the DNA change (e.g. through splicing disruption as assessed by at least computational analysis) instead of through the amino acid change)
PM1 is not applicable because the VCEP's only PM1 specification is for missense variants in the KCNQ4 pore-forming region at amino acids 271-292. This case is a GJB2 frameshift variant at Gly12, and the authoritative domain_tables entry is empty; no GJB2 PM1 region or applicable hotspot route is specified by this VCEP.
Mutational hot spot or well-studied functional domain without benign variation (KCNQ4 pore-forming region). * KCNQ4 (NM_004700.4) gene - missense variants located within amino acids 271-292 can be awarded PM1. This region is the pore-forming intramembrane region where many variants that cause autosomal dominant hearing loss are located (Naito et al. 2013, PMID: 23717403; https://www.uniprot.org/uniprot/P56696). There are only two missense variants in this region in gnomAD, each with only single allele (http://gnomad.broadinstitute.org/; rs763326539: 1/33578 Latino chromosomes; rs55737429: 1/111720 European chromosomes).
PM4 is limited by the VCEP to protein length change caused by an in-frame deletion or insertion outside repetitive regions. This variant is a frameshift deletion, not an in-frame deletion or insertion, so PM4 does not apply.
Protein length change due to an in-frame deletion or insertion that are not located in repetitive regions. * No changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group.
PM5 is not applicable because the case variant is a frameshift, not a missense change. The VCEP PM5 specification requires a missense change at the same codon as one or two different pathogenic missense variants; the rule therefore does not apply to NM_004004.6:c.35del / p.(Gly12ValfsTer2).
Missense change at same codon as another pathogenic missense variant. No changes. Follow recommendations as outlined in ACMG/AMP guidelines and/or Sequence Variant Interpretation working group.
The ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2.0 marks PP2 as not applicable. The VCEP states: "Advise against using this rule because there are few such genes that this would apply to, particularly genes associated to autosomal recessive hearing loss." NM_004004.6:c.35del in GJB2 is a frameshift variant predicted to produce NP_003995.2:p.(Gly12ValfsTer2). This determination was made deterministically from the VCEP criteria specification, prior to LLM adjudication.
deterministic_prefilter: vcep_not_applicable
The ClinGen Hearing Loss Expert Panel Version 2.0 rule limits PP3 to missense variants evaluated with REVEL or splice variants evaluated with MaxEntScan, with a predicted splice impact supporting PP3. NM_004004.6:c.35del in GJB2 is a coding frameshift, NP_003995.2:p.(Gly12ValfsTer2), and is neither a missense variant nor a splice-site variant in the governing rule's specified situation. Therefore PP3 is not applicable. The available SpliceAI result is not used because SpliceAI is not the predictor named by this VCEP rule for this situation.
REVEL score ≥0.7, or predicted impact to splicing using MaxEntScan. * Use REVEL and MAXENTSCAN. * For missense variants, award PP3 if REVEL score is ≥0.7. * If splicing is predicted to be impacted, either creation of a cryptic splice site, or disruption of a native splice site, award PP3. * For splice variants (except for canonical -/+1 or 2), use MAXENTSCAN. * For -/+ 1 or 2 splice variants, do not use PP3 if you are using PVS1.
The ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2.0 marks BP1 as not applicable. NM_004004.6:c.35del in GJB2 is a frameshift variant predicted to produce NP_003995.2:p.(Gly12ValfsTer2). This determination was made deterministically from the VCEP criteria specification, prior to LLM adjudication.
deterministic_prefilter: vcep_not_applicable
BP3 is limited by the VCEP to in-frame indels in a repeat region without known function. This variant is a frameshift deletion, not an in-frame indel, so BP3 does not apply; repeat-region status cannot change that variant-type exclusion.
In-frame indels in repeat region without known function. No changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group.
The ClinGen Hearing Loss Expert Panel Version 2.0 BP4 rule concerns computational evidence suggesting no impact through a REVEL score or no impact to splicing in MaxEntScan. NM_004004.6:c.35del is a frameshift variant, NP_003995.2:p.(Gly12ValfsTer2). For a frameshift, a no-impact splice prediction would not negate the truncating protein effect; accordingly BP4 is not applicable. The available SpliceAI result is not used because the governing BP4 rule names MaxEntScan, and in any event it cannot establish no impact of this frameshift on the gene product.
Computational evidence suggests no impact; REVEL score ≤0.15 or no impact to splicing in MaxEntScan.
The VCEP BP5 rule limits use to variants in an autosomal-dominant gene and explicitly states not to use it for autosomal-recessive disease because an individual may be a carrier of a pathogenic variant and have an alternate cause. GJB2-related nonsyndromic hearing loss in the governing framework is autosomal recessive, so BP5 is not applicable regardless of any alternate diagnosis.
Variant in an autosomal dominant gene found in a patient with an alternate explanation. * Autosomal recessive: Do not use. An individual could be carrier of pathogenic variant and have an alternate cause. Therefore, BP5 shouldn’t be used as evidence for benign in this case.
The Hearing Loss VCEP marks BP6 as not applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. A benign report from a reputable source cannot be converted into BP6 under this VCEP framework.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The ClinGen Hearing Loss Expert Panel Version 2.0 BP7 rule applies to silent variants with no predicted impact to splicing. NM_004004.6:c.35del in GJB2 is a coding frameshift, NP_003995.2:p.(Gly12ValfsTer2), not a silent variant. Therefore BP7 is not applicable, and no splice predictor result is needed to reach that determination.
Silent variant with no predicted impact to splicing. No changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group.
Every interpreted variant in GJB2, mapped onto the exon structure of NM_004004.6. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (Finnish)607 / 63,974 | 0.00956 hom |
| European (non-Finnish)9758 / 1,179,762 | 0.008330 hom |
| Remaining individuals416 / 62,494 | 0.00671 hom |
| Admixed American310 / 59,958 | 0.0052 |
| Middle Eastern25 / 6,058 | 0.0041 |
| Ashkenazi Jewish107 / 29,606 | 0.0036 |
| Amish2 / 912 | 0.0022 |
| African/African American94 / 74,862 | 0.00131 hom |
| South Asian55 / 91,008 | 0.0006 |
| East Asian1 / 44,848 | 2.2e-05 |
| European (non-Finnish)1217 / 127,068 | 0.00964 hom |
| European (Finnish)210 / 25,124 | 0.00846 hom |
| Remaining individuals55 / 7,206 | 0.0076 |
| Admixed American169 / 35,434 | 0.0048 |
| Ashkenazi Jewish35 / 10,362 | 0.0034 |
| African/African American26 / 24,940 | 0.001 |
| South Asian25 / 30,612 | 0.00082 |
This variant is present in gnomAD v4.1 (AF= 0.00704997; MAF= 0.70500%, 11375/1613482 alleles, homozygotes = 38) and has highest observed frequency in the European (Finnish) population (AF= 0.00948823; MAF= 0.94882%, 607/63974 alleles, homozygotes = 6); grpmax FAF= 0.0081339.
This variant is present in gnomAD v2.1 (AF= 0.00618819; MAF= 0.61882%, 1737/280696 alleles, homozygotes = 10) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00957755; MAF= 0.95775%, 1217/127068 alleles, homozygotes = 4); grpmax FAF= 0.0109023.
This variant is present in gnomAD-Canada v1.0 (AF= 0.006893931169254153, 127/18422 alleles, homozygotes = 1).
The ClinGen Hearing Loss Expert Panel Version 2.0 rule limits PP3 to missense variants evaluated with REVEL or splice variants evaluated with MaxEntScan, with a predicted splice impact supporting PP3. NM_004004.6:c.35del in GJB2 is a coding frameshift, NP_003995.2:p.(Gly12ValfsTer2), and is neither a missense variant nor a splice-site variant in the governing rule's specified situation. Therefore PP3 is not applicable. The available SpliceAI result is not used because SpliceAI is not the predictor named by this VCEP rule for this situation.
REVEL score ≥0.7, or predicted impact to splicing using MaxEntScan. * Use REVEL and MAXENTSCAN. * For missense variants, award PP3 if REVEL score is ≥0.7. * If splicing is predicted to be impacted, either creation of a cryptic splice site, or disruption of a native splice site, award PP3. * For splice variants (except for canonical -/+1 or 2), use MAXENTSCAN. * For -/+ 1 or 2 splice variants, do not use PP3 if you are using PVS1.
The ClinGen Hearing Loss Expert Panel Version 2.0 BP4 rule concerns computational evidence suggesting no impact through a REVEL score or no impact to splicing in MaxEntScan. NM_004004.6:c.35del is a frameshift variant, NP_003995.2:p.(Gly12ValfsTer2). For a frameshift, a no-impact splice prediction would not negate the truncating protein effect; accordingly BP4 is not applicable. The available SpliceAI result is not used because the governing BP4 rule names MaxEntScan, and in any event it cannot establish no impact of this frameshift on the gene product.
Computational evidence suggests no impact; REVEL score ≤0.15 or no impact to splicing in MaxEntScan.
The ClinGen Hearing Loss Expert Panel Version 2.0 BP7 rule applies to silent variants with no predicted impact to splicing. NM_004004.6:c.35del in GJB2 is a coding frameshift, NP_003995.2:p.(Gly12ValfsTer2), not a silent variant. Therefore BP7 is not applicable, and no splice predictor result is needed to reach that determination.
Silent variant with no predicted impact to splicing. No changes. Follow recommendations as outlined in Richard 2015 and/or ClinGen's Sequence Variant Interpretation working group.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
10 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Here, we report the frequency of GJB2 alleles in the Italian population affected by hearing loss and the functional analysis of six missense mutations. Genetic studies indicate that, apart from the common 35delG, only few additio
PubMed abstract, available abstract snippet
35delG is the most commonly identified mutation in the GJB2 gene. This mutation causes a deletion of a single G in a string of 6 and is reliably identified by the SNHL array in both the forward and reverse direction.
Results, Figure 2B; Synthetic Validation Controls paragraph
In this study, they accounted for 22 % of all diagnoses and 26 % of diagnoses in the congenital severe-to-profound ARNSHL cohort.
Discussion, paragraph beginning “In many of the world’s populations, variants in GJB2...” and Table 2
Premature termination codons (PTC), such as c.35delG, c.167delT, and c.235delC common in European, Ashkenazi Jewish, and Asian populations respectively, are established pathogenic variants.
Introduction; Table 4, c.[35delG];[35delG] genotype row
The probands in families 10 (IV.3) and 11 (IV.3) revealed a prevalent homozygous pathogenic frameshift variant c.35delG, p.(Gly12Valfs*2) [40] that segregated in both families (Figure 1).
Results, section 3.3.1 GJB2; Table 1, families 10 and 11
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 0.00704997; MAF= 0.70500%, 11375/1613482 alleles, homozygotes = 38) and has highest observed frequency in the European (Finnish) population (AF= 0.00948823; MAF= 0.94882%, 607/63974 alleles, homozygotes = 6); grpmax FAF= 0.0081339.
This variant is present in gnomAD v2.1 (AF= 0.00618819; MAF= 0.61882%, 1737/280696 alleles, homozygotes = 10) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00957755; MAF= 0.95775%, 1217/127068 alleles, homozygotes = 4); grpmax FAF= 0.0109023.
This variant is present in gnomAD-Canada v1.0 (AF= 0.006893931169254153, 127/18422 alleles, homozygotes = 1).
This variant has been reported in ClinVar as Pathogenic (93 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Hearing Loss Variant Curation Expert Panel (expert panel). (ClinVarID = 17004)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06).
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV101241530, n = 1 times).
This variant does not lie in a statistically significant hotspot.