Variant classification summary

NM_004004.6:c.35del

GJB2 · NP_003995.2:p.(Gly12ValfsTer2) · NM_004004.6

GRCh37: chr13:20763685 AC>A · GRCh38: chr13:20189546 AC>A

Gene: GJB2 Transcript: NM_004004.6

Final call

Benign

PVS1 very strong PP5 supporting BA1 stand-alone benign BS1 strong

Variant details

Gene

GJB2

Transcript

NM_004004.6

Protein

NP_003995.2:p.(Gly12ValfsTer2)

gnomAD AF

0.007049970188697488 (v4.1)

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 very strong: the early frameshift truncates GJB2 at residue 13 instead of 227.

2

PP5 supporting: the ClinGen Hearing Loss Expert Panel classification called the variant pathogenic.

3

BA1 stand-alone benign: gnomAD frequency is 0.705%, exceeding the VCEP recessive threshold of 0.5%.

4

BS1 strong: gnomAD frequency is 0.705%, exceeding the VCEP recessive threshold of 0.3%.

Final determination: Under the VCEP criterion rules and ACMG/AMP 2015 Table 5, BA1 alone satisfies the benign rule, while PVS1 plus one supporting criterion does not satisfy a pathogenic rule.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	Met, very strong: the exon-2 frameshift truncates GJB2 at residue 13 instead of the 227-residue reference protein.	cspec pvs1_variant_assessment
PS1	N/A	Not applicable: c.35del produces p.(Gly12ValfsTer2), a frameshift rather than the VCEP-defined same-amino-acid or same-nucleotide splice scenario.	cspec
PS2	Not assessed	Not assessed: no affected-proband occurrence with confirmed de novo origin and both maternity and paternity documented.
PS3	Not assessed	Not assessed: no variant-specific GJB2 electrical-coupling or dye-transfer result for c.35del is available against both negative and wild-type controls.	cspec PMID:12176036
PS4	Not assessed	Not assessed: available papers lack case/control counts or a calculable odds ratio and confidence interval required by the VCEP PS4 rule.	cspec PMID:33187236 PMID:16950989 PMID:31160754 PMID:26969326
PM1	N/A	Not applicable: the VCEP specifies PM1 only for KCNQ4 missense variants at residues 271-292, whereas this is a GJB2 Gly12 frameshift.	cspec
PM2	Not met	Not met: all-comers gnomAD v4.1 AF 0.00704997 (0.70500%) exceeds the VCEP PM2 autosomal-recessive cutoff of 0.00007 (0.007%).	cspec gnomad_v2 gnomad_v4
PM3	Not met	Not met: gnomAD v4.1 AF 0.00704997 exceeds the VCEP PM2_Supporting threshold of 0.00007 required for the homozygous PM3 path.	cspec gnomad_v4 PMID:33187236
PM4	N/A	Not applicable: c.35del is a frameshift deletion, whereas PM4 requires an in-frame indel outside a repetitive region.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: c.35del is a Gly12 frameshift, but PM5 requires a missense change at the same codon as pathogenic missense variants.	cspec
PM6	Not assessed	Not assessed: no affected-proband occurrence is documented as assumed de novo without parental origin confirmation.
PP1	Not assessed	Not assessed: segregation is reported in two families, but the number of affected relatives required by the recessive PP1 thresholds is not enumerated.	cspec PMID:33187236
PP2	N/A	Not applicable: the VCEP excludes PP2 for this gene.	cspec
PP3	N/A	Not applicable: c.35del is a coding frameshift, outside the VCEP PP3 paths for missense REVEL or splice-variant MaxEntScan assessment.	cspec
PP4	Not assessed	Not assessed: patient-specific phenotype and the VCEP Table 7 specifications are unavailable, so phenotype specificity cannot be evaluated.	cspec
PP5	Met	Not applicable: the Hearing Loss VCEP explicitly excludes PP5 from use.	cspec clinvar
BA1	Met	Met: all-comers gnomAD v4.1 AF 0.00704997 (0.70500%) exceeds the VCEP autosomal-recessive BA1 threshold of 0.005 (0.5%).	cspec gnomad_v2 gnomad_v4
BS1	Met	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%).	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports 38 homozygotes, but does not establish unaffected controls or biallelic genotypes with a known pathogenic variant in trans.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no c.35del GJB2 assay shows function comparable to wild type against the specified negative control.	cspec PMID:12176036
BS4	Not assessed	Not assessed: no qualifying phenotype-positive/genotype-negative or genotype-positive/phenotype-negative relative with diagnostic audiometry is documented.	cspec
BP1	N/A	Not applicable: the VCEP excludes BP1 for this gene.	cspec
BP2	Not assessed	Not assessed: no documented cis or trans phase with a pathogenic or dominant variant is available for the VCEP BP2 requirement.	cspec PMID:33187236
BP3	N/A	Not applicable: c.35del is a frameshift deletion, while BP3 requires an in-frame indel in a repeat region without known function.	cspec pvs1_variant_assessment
BP4	N/A	Not applicable: BP4 cannot evaluate a no-impact splice prediction for this frameshift because the truncating protein effect remains.	cspec
BP5	N/A	Not applicable: the VCEP says not to use BP5 for autosomal-recessive disease, which governs GJB2 here.	cspec
BP6	N/A	Not applicable: the Hearing Loss VCEP explicitly excludes BP6 from use.	cspec
BP7	N/A	Not applicable: BP7 is limited to silent variants, whereas c.35del is a coding frameshift producing p.(Gly12ValfsTer2).	cspec

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