The SLC26A4 NM_000441.2:c.919-2A>G (NP_000432.1:p.?) splicing variant has not previously been reported in somatic cancers (COSMIC). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS). This variant is considered to be Pathogenic by the VCEP (ClinGen Hearing Loss Variant Curation Expert Panel; ClinVar ID 4840).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.SLC26A4 encodes a protein related to sulfate transporters and is involved in transporting ions across cell membranes. Loss-of-function changes in this gene cause Pendred syndrome, an autosomal-recessive disorder characterized mainly by syndromic hearing loss and often thyroid abnormalities. SLC26A4 is not established as a cancer-related gene.
The recorded framework is ClinGen SLC26A4 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 at very strong: exact-variant RT-PCR showed complete exon 8 skipping, causing an 83-nucleotide frameshift and premature termination in SLC26A4.
Met at Moderate strength: affected patients had compound-heterozygous p.H723R/c.919-2A>G genotypes, documenting the target allele in trans with the disease allele.
Met supporting: the splice-site variant segregates with hearing loss in affected relatives, satisfying the VCEP threshold of one affected relative for recessive disease.
Not applicable: this VCEP explicitly prohibits PP5, regardless of pathogenic reports for c.919-2A>G.
Met: gnomAD v2.1 East Asian AF 0.00506367 exceeds the VCEP autosomal-recessive BA1 threshold of 0.005 (0.5%).
Met strong: gnomAD v2.1 East Asian AF 0.00506367 exceeds the VCEP autosomal-recessive BS1 Strong threshold of 0.003 (0.3%).
VUS: PVS1 (very strong), PM3 (moderate), PP1 and PP5 (supporting) conflict with BA1 (stand-alone benign) and BS1 (strong).
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 125 / 1,613,754 alleles. Recorded AF 7.74591e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0.000364718; MAF= 0.03647%, 103/282410 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00506367; MAF= 0.50637%, 101/19946 alleles, homozygotes = 0); grpmax FAF= 0.00492851.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.998. Refer to the recorded PP3/BP4 rationale for interpretation.
27 Pathogenic · 1 Affects. ClinVar API review status: reviewed by expert panel.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
ACMG/AMP criteria under ClinGen SLC26A4 VCEP v2.0, with the data and sources behind each one.
28 criteria with recorded statuses: 6 met · 5 not met · 8 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
For the requested consequence-of-function criteria only, PVS1 is met at very strong strength; PM4 and BP3 are not applicable because the variant is a canonical splice-site substitution rather than an in-frame indel.
Only the VCEP's own Version 2.0 rules were applied. PS4 and PP4 remain not assessed because their required case-control/statistical or Table 7 phenotype-specificity inputs are unavailable; PP5, BP5, and BP6 are not applicable under explicit VCEP restrictions.
The available literature includes affected-family and affected-cohort observations, but these do not substitute for the VCEP's PS4 case-control requirement or PP4 Table 7 phenotype-specificity assessment.
The governing framework is the ClinGen Hearing Loss Expert Panel Version 2.0 specification for SLC26A4.
Only predictors explicitly named by the governing criterion rule were eligible: REVEL and MaxEntScan; SpliceAI was not substituted for either.
The variant is a canonical -2 splice-site variant, so BP7 is outside scope and PP3 has a VCEP-specific interaction with PVS1 use.
No criteria match.
NM_000441.2:c.919-2A>G is a canonical acceptor splice variant at -2 of exon 8 in SLC26A4. The affected transcript is the MANE transcript, and skipping exon 8 removes 83 coding nucleotides, shifts the reading frame, and is predicted to cause premature termination; the affected exon is internal (exon 8 of 21), not the first, last, or penultimate exon. RT-PCR for this exact variant demonstrated complete exon 8 skipping with a frameshift and premature termination. A separate study detected residual normally spliced transcript, but the governing VCEP text provides no named downgrade rule for a leaky canonical splice variant, and no specific downgrade rule is established in the supplied VCEP criteria. SLC26A4 is eligible under the VCEP PVS1 gene gate because loss of function is an established disease mechanism. Therefore PVS1 is met at full strength: very strong.
Null variant in a gene with established LOF as a disease mechanism; see PVS1_Strong, PVS1_Moderate, PVS1_Supporting for reduced evidence applications.
PM3 is met at Moderate strength. In an affected cohort of 111 Korean patients with bi-allelic SLC26A4 mutations and bilateral enlarged vestibular aqueduct with hearing loss, the study specifically analyzed patients with compound heterozygous p.H723R/c.919-2A>G genotypes. A compound-heterozygous genotype documents the target allele in trans with the p.H723R disease allele in affected individuals. This satisfies the VCEP example for one PM3 point: detected in trans with a pathogenic variant in a recessive disorder.
1 point awarded from tables 7a and 7b. Example: Detected in trans with a pathogenic variant (recessive).
The variant is reported with phenotype-consistent hearing loss in affected relatives in multiple family reports. PMID:10874637 describes the splice-site mutation in an extended inbred Pendred syndrome family, including two affected siblings with the splice-site allele and a second mutation; PMID:11502831 reports affected members of a Pendred syndrome family carrying the variant; and PMID:16711435 reports affected twin sisters with DVAS and hearing loss with hearing-normal parents. This establishes segregation in at least one affected relative, meeting the VCEP supporting threshold, but the available extracted records do not provide a sufficiently auditable pedigree-level count and phase assessment for a higher strength.
Segregation in one affected relative for recessive and two affected relatives for dominant.
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 for an autosomal-recessive variant at MAF >=0.005 (0.5%). SLC26A4 is governed here as autosomal recessive. In gnomAD v2.1, the highest observed population frequency is East Asian AF 0.005063671914168255 (101/19,946 alleles; 0 homozygotes), which exceeds 0.005. gnomAD v4.1 reports a lower East Asian AF of 0.00263005393839433, but the v2.1 population observation independently reaches the VCEP BA1 threshold. No VCEP rule requires the frequency to be present in every population dataset or requires exclusion of the observed ancestry-specific maximum.
MAF of ≥0.005 (0.5%) for autosomal recessive; MAF of ≥0.001 (0.1%) for autosomal dominant.
The Hearing Loss VCEP specifies BS1 Strong for an autosomal-recessive variant at MAF ≥0.003 (0.3%), provided there is no conflicting evidence. SLC26A4 is autosomal recessive, and the gnomAD v2.1 East Asian frequency is 0.005063671914168255 (101/19,946 alleles; 0 homozygotes), exceeding 0.003. gnomAD v4.1 reports a lower East Asian AF of 0.00263005393839433, but the v2.1 observation meets the stated threshold. The VCEP text does not require concordance across databases or prohibit use of an ancestry-specific maximum.
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.
No de novo occurrence is documented. The available family reports describe the splice-site variant in affected siblings or multiple affected relatives, with parental or familial inheritance information, rather than a proven de novo event. Therefore the VCEP PS2 de novo point thresholds are not reached.
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. ... 2 points per tables 5a and 5b: Examples: 1 proven de novo occurrence; OR 2 assumed de novo occurrences. ... 1 point per tables 5a and 5b: Examples: 1 proven de novo occurrence (phenotype consistent but not specific to gene); OR 1 assumed de novo occurrence; OR 2 assumed de novo occurrences (phenotype/gene not specific). ... 0.5 points per tables 5a and 5b: Example: 1 assumed de novo occurrence (phenotype/gene not specific).
The Hearing Loss VCEP permits PM2 at Supporting strength for an autosomal-recessive variant that is absent or has MAF <=0.00007 (0.007%). The all-comers gnomAD v2.1 total AF is 0.0003647179632449276 and the gnomAD v4.1 total AF is 0.00007745914185185598; both exceed 0.00007. The ancestry-specific frequencies are also higher, including East Asian AF 0.005063671914168255 in v2.1 and 0.00263005393839433 in v4.1. Thus the VCEP PM2 Supporting cutoff is not met.
Absent/Rare in population databases (absent or ≤0.00007 (0.007%) for autosomal recessive, ≤0.00002 (0.002%) for autosomal dominant).
No assumed de novo occurrence is documented. The available reports provide familial segregation and parental observations rather than an affected proband whose variant status in both parents is untested or otherwise only assumed de novo. The VCEP directs PM6 to the PS2 framework, so no PM6 point threshold is reached.
See PS2 above
The Hearing Loss VCEP requires observation of the variant biallelic with a known pathogenic variant in controls in a manner inconsistent with disease penetrance. gnomAD v2.1 and gnomAD v4.1 each report zero homozygotes for this variant, and no control observation biallelic with a known pathogenic variant is available in the population evidence. Therefore the specified BS2 observation is not present.
Observation of variant (biallelic with known pathogenic variant for recessive) in controls inconsistent with disease penetrance. ... However, if biallelic observations in controls are inconsistent with disease penetrance, this may be applicable.
No qualifying non-segregation is documented. The reports describe affected relatives carrying the variant and unaffected parents in recessive families, which is compatible with carrier status and is not genotype-positive/phenotype-negative evidence for the recessive disease. No affected-family member is documented to lack the variant, and no confidently unaffected individual is documented to carry biallelic disease-causing alleles.
Non-segregation with disease.
The VCEP permits PS1 for a splice variant at the same nucleotide as a previously reported pathogenic variant when the impact prediction is similar, with assessment of possible direct DNA-level effects. The available evidence confirms that NM_000441.2:c.919-2A>G is a canonical splice variant and is pathogenic, but it does not identify a different pathogenic nucleotide substitution at c.919-2 or provide a comparator impact prediction. Therefore the VCEP splice-specific PS1 route cannot be evaluated.
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)
The available studies provide variant-specific RNA evidence for a deleterious splice effect, but the VCEP's SLC26A4 PS3 path is restricted to radio-isotope or fluorescence assays. PMID:15574297 reports complete exon 8 skipping, a frameshift, and premature termination by RT-PCR, and PMID:24007330 reports reduced normal transcript (approximately 6% of normal in nasal mucosa and 17% in lymphocytes) with both normal and exon-8-skipped transcripts. However, no qualifying radio-isotope result showing statistically significant decreased iodide efflux or fluorescence result showing a statistically significant ΔFmax% difference from wild type and no significant difference from empty vector is available. The VCEP's separately stated allowance for other functional analyses is framed for other genes/functional analyses, not as an alternative SLC26A4 assay path; therefore PS3 cannot be assigned from these RNA studies under the governing rule.
SLC26A4: Radio isotope and fluorescence assays → PS3_Supporting * Radio Isotope Assays: PS3_Supporting would be applied when cells transfected with mutant SLC26A4 show a statistically significant decreased efflux of iodide compared to wildtype pendrin. * Fluorescence Assays: PS3_Supporting would be applied when a cell transfected with the mutant SLC26A4 shows a statistically significant difference in fluorescence (ΔFmax %) compared to the wildtype protein, and when the fluorescence is not significantly different from that of an empty vector control.
The VCEP's strong PS4 rule requires a Fisher Exact or Chi-Squared analysis showing a statistical increase in cases over controls, or an autosomal-dominant proband-count route. SLC26A4 is specified here as autosomal recessive, so the dominant count routes do not apply. The reviewed literature includes affected cohorts and family reports, including 111 Korean patients with biallelic SLC26A4 variants and c.919-2A>G in 24% of alleles, but no matched control count, case-control table, or reported statistical test for this exact variant was available; therefore an odds ratio, confidence interval, and Fisher/Chi-Squared result cannot be established. The literature_pass PS4 index was also checked: its listed PS4 PMIDs were not in the already-read AI-classified-paper set, and no qualifying case-control result was verified from the available paper extracts.
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.
NM_000441.2:c.919-2A>G is a canonical -2 splice variant. The VCEP PP3 rule requires MaxEntScan for splice variants and states not to use PP3 for canonical -/+1 or 2 splice variants when PVS1 is being used. SpliceAI max delta 0.998 predicts splice impact, but SpliceAI is not the predictor named by this rule, and the available group evidence does not establish whether PVS1 is being used; therefore PP3 cannot be resolved under the governing rule.
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 VCEP requires the patient's phenotype to be highly specific for the gene or a fully sequenced gene set and directs the evaluator to specifications in Table 7. The available CSPEC criteria entry contains the PP4 rule but does not provide the referenced Table 7 specifications, and the case evidence available here does not provide a complete patient phenotype or a documented fully sequenced gene-set evaluation. A specific PP4 determination therefore cannot be made without the VCEP's Table 7 criteria and complete phenotype data.
Patient's phenotype highly specific for gene or fully sequenced gene set (see specifications in Table 7).
No available study demonstrates a benign functional result for c.919-2A>G. The available variant-specific RNA studies instead report abnormal splicing: complete exon 8 skipping with frameshift and premature termination in PMID:15574297, and markedly reduced normal transcript with exon-8-skipped transcript in PMID:24007330. The VCEP's SLC26A4 BS3 supporting rule requires radio-isotope iodide efflux comparable to wild type or fluorescence comparable to wild type; neither result is reported. BS3 therefore cannot be assigned.
* 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
BP2 cannot be assessed from the available evidence. The SLC26A4 VCEP rule requires observation in trans with a dominant variant or observation in cis with a pathogenic variant, with caution for genes associated with both dominant and recessive hearing loss. The available reports document compound heterozygous or homozygous SLC26A4 genotypes but do not document the target allele in trans with a dominant variant or in cis with a pathogenic variant.
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.
The VCEP BP4 rule permits computational no-impact evidence through REVEL <=0.15 or no impact to splicing in MaxEntScan. REVEL is unavailable, and no MaxEntScan result is available. SpliceAI max delta 0.998 predicts splice impact but is not the predictor named by the governing rule, so BP4 cannot be assessed from the available rule-valid evidence.
Computational evidence suggests no impact; REVEL score ≤0.15 or no impact to splicing in MaxEntScan.
The VCEP's only PM1 specification in the governing CSPEC is limited to missense variants in the KCNQ4 pore-forming region at amino acids 271-292. This case is SLC26A4 c.919-2A>G, a canonical splice variant, and vcep_materials.json contains no SLC26A4 domain-table entry. The specified KCNQ4 route therefore does not apply.
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).
The variant is a canonical splice-site substitution, not an in-frame deletion or insertion producing a protein length change. The PM4 rule therefore 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.
The VCEP PM5 rule is restricted to a missense change at the same codon as one or more pathogenic missense variants. This case is NM_000441.2:c.919-2A>G, a canonical splice variant with protein consequence p.?, so it has no amino-acid codon or residue on which the PM5 rule can operate. The PM5 candidate collection likewise found no eligible same-residue missense candidates.
Missense change at same codon as two different pathogenic missense variants. * Located at an amino acid residue with known pathogenic variation (at least 2 other variants at the same site meet pathogenic criteria for based on independent data) * Caveat: Assess whether the variants in question could have an impact at the DNA level, such as through splicing impacts. 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_000441.2:c.919-2A>G in SLC26A4 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000432.1:p.?. 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 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_000441.2:c.919-2A>G in SLC26A4 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000432.1:p.?. This determination was made deterministically from the VCEP criteria specification, prior to LLM adjudication.
deterministic_prefilter: vcep_not_applicable
The variant is a canonical splice-site substitution, not an in-frame indel. It therefore does not meet the VCEP's variant-type applicability requirement for BP3, regardless of whether a repeat region is documented.
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 VCEP BP5 rule states that an autosomal-recessive variant in a patient with an alternate cause must not receive BP5, because the individual could be a carrier of a pathogenic variant and have an alternate cause. SLC26A4 is specified as autosomal recessive in the governing VCEP framework, so BP5 is not applicable even if an alternate explanation were documented.
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. * Autosomal dominant: Can use BP5 as outlined by Richards 2015. * Caveat: consider whether multiple pathogenic autosomal dominant variants could cause a more severe phenotype or whether multigenic inheritance is known to occur (example: Bardet-Biedl syndrome).
The VCEP marks BP6 as not applicable for this VCEP and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Reputable-source classifications therefore cannot be used to apply BP6 under the governing framework.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BP7 is limited by the VCEP rule to silent variants with no predicted impact to splicing. NM_000441.2:c.919-2A>G is a canonical intronic splice-site variant with predicted protein consequence p.?, not a silent coding variant; BP7 is therefore outside its governing scope.
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 SLC26A4, mapped onto the exon structure of NM_000441.2. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| East Asian118 / 44,866 | 0.0026 |
| Middle Eastern1 / 6,060 | 0.00017 |
| Remaining individuals3 / 62,488 | 4.8e-05 |
| South Asian1 / 91,080 | 1.1e-05 |
| European (non-Finnish)2 / 1,179,700 | 1.7e-06 |
| East Asian101 / 19,946 | 0.0051 |
| European (non-Finnish)2 / 128,880 | 1.6e-05 |
This variant is present in gnomAD v4.1 (AF= 7.74591e-05; MAF= 0.00775%, 125/1613754 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00263005; MAF= 0.26301%, 118/44866 alleles, homozygotes = 0); grpmax FAF= 0.0022441.
This variant is present in gnomAD v2.1 (AF= 0.000364718; MAF= 0.03647%, 103/282410 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00506367; MAF= 0.50637%, 101/19946 alleles, homozygotes = 0); grpmax FAF= 0.00492851.
Not available in gnomAD-Canada v1.0.
NM_000441.2:c.919-2A>G is a canonical -2 splice variant. The VCEP PP3 rule requires MaxEntScan for splice variants and states not to use PP3 for canonical -/+1 or 2 splice variants when PVS1 is being used. SpliceAI max delta 0.998 predicts splice impact, but SpliceAI is not the predictor named by this rule, and the available group evidence does not establish whether PVS1 is being used; therefore PP3 cannot be resolved under the governing rule.
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 VCEP BP4 rule permits computational no-impact evidence through REVEL <=0.15 or no impact to splicing in MaxEntScan. REVEL is unavailable, and no MaxEntScan result is available. SpliceAI max delta 0.998 predicts splice impact but is not the predictor named by the governing rule, so BP4 cannot be assessed from the available rule-valid evidence.
Computational evidence suggests no impact; REVEL score ≤0.15 or no impact to splicing in MaxEntScan.
BP7 is limited by the VCEP rule to silent variants with no predicted impact to splicing. NM_000441.2:c.919-2A>G is a canonical intronic splice-site variant with predicted protein consequence p.?, not a silent coding variant; BP7 is therefore outside its governing scope.
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 possible splice impact for this variant (max delta score = 1.00). BayesDel score = 0.66.
8 paper records listed. 5 cited in the classification.
The majority of patients in this family are homozygous for a splice site mutation (1143-2A-->G) affecting the 3' splice site consensus sequence of intron 7. However, two affected sibs with non-consanguineous parents are compound heterozygotes for the splice site mutation and a missense mutation (1558T-->G), substituting an evolutionarily conserved
Location Abstract
Context Extended inbred Turkish Pendred syndrome family with molecular analysis of PDS mutations and affected-relative observations.
In family I, two siblings were deaf, and one was normal. In family II, both parents and two offspring were deaf.
Location Abstract
Context Two Chinese Pendred syndrome families assessed by clinical examination, temporal-bone CT, and molecular analysis of the pendrin gene.
Deletion of the exon 8 results in frameshift and premature termination of translation.
Location Abstract, lines 20–21; Results, Fig. 4 description, lines 291–296
Context RT-PCR analysis of RNA from patients with SLC26A4-related hearing loss and splice-site mutations.
The twin sisters from pedigree and the brother and sister from pedigree 2 all suffered from sensorineural hearing loss. All patients from these two families were confirmed to have enlarged vestibular aqueduct by temporal bone CT scan.
Location Abstract
Context Two familial DVAS pedigrees assessed by temporal-bone CT, direct sequencing of exons 7 and 8 with flanking regions, and DHPLC screening of other exons.
In two patients homozygous for c.919-2A>G, RNA analysis detected both transcripts lacking exon 8 and normally spliced transcripts; normal transcripts were approximately 6% of normal in nasal mucosa and 17% in lymphocytes.
Location Results, mRNA transcripts in patients with c.919-2A>G homozygous mutation; Discussion
Context 111 Korean patients from 100 unrelated families with biallelic SLC26A4 mutations; RT-PCR, sequencing, and quantitative real-time PCR of nasal mucosa and lymphocyte RNA from two homozygous individuals.
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= 7.74591e-05; MAF= 0.00775%, 125/1613754 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00263005; MAF= 0.26301%, 118/44866 alleles, homozygotes = 0); grpmax FAF= 0.0022441.
This variant is present in gnomAD v2.1 (AF= 0.000364718; MAF= 0.03647%, 103/282410 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00506367; MAF= 0.50637%, 101/19946 alleles, homozygotes = 0); grpmax FAF= 0.00492851.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (27 clinical laboratories) and as Affects (1 clinical laboratory) and as Pathogenic by ClinGen Hearing Loss Variant Curation Expert Panel (expert panel). (ClinVarID = 4840)
SpliceAI predicts possible splice impact for this variant (max delta score = 1.00). BayesDel score = 0.66.
This variant has not previously been reported in somatic cancers (COSMIC).