13-20189299-C-T

Variant names:

• chr13-20189299-C-T
• rs111033299
• NM_004004.6:c.283G>A
• GJB2 p.Val95Met

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 15 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2_SupportingPM5PP3_ModeratePP5_Strong

The NM_004004.6(GJB2):c.283G>A (p.Val95Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000483 (AC=78) in the gnomAD database across 1,613,992 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000215. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002511670: One publication reports that the variant negatively impacted large molecule trafficking across gap junctions, thereby disrupting gap junction mediated intracellular signaling (Zhang_2005)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.V95A: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 496217) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.V95L: VUS-low (ClinVar VariationId 4856990, 1 star) This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Deafness, autosomal recessive, 1A (DFNB1A); it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000045 (0 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 2.15
• Publications: 37 publications found

Genes affected

GJB2 (HGNC:4284): (gap junction protein beta 2) This gene encodes a member of the gap junction protein family (gap junction beta 2) but is more commonly known as connexin 26. The gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. Connexins form hexameric channels in the plasma membrane which regulate passage of ions and small molecules between the cell and its environment or, when joined with another cell, form a dodecameric intercellular gap junction channel. The connexin proteins are grouped into alpha, beta, and gamma subfamilies. Mutations in this gene are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Mar 2026]

GJB2 Gene-Disease associations (from GenCC):

• Bart-Pumphrey syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• hearing loss disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• ichthyosis, hystrix-like, with hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
• keratoderma hereditarium mutilans

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• palmoplantar keratoderma-deafness syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• autosomal recessive nonsyndromic hearing loss 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant keratitis-ichthyosis-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, PanelApp Australia
• autosomal dominant nonsyndromic hearing loss 3A

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• KID syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296095 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Specifications for GJB2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 15 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV002511670: One publication reports that the variant negatively impacted large molecule trafficking across gap junctions, thereby disrupting gap junction mediated intracellular signaling (Zhang_2005).; SCV000603835: Functional studies suggest the variant protein affects biochemical coupling, but has little or no effect on intercellular conductance of gap junctions (Zhang 2005, Wang 2003).; SCV000936055: Experimental studies have shown that this missense change affects GJB2 function (PMID: 16217030).; SCV001871336: "Published functional studies demonstrate a damaging effect on the ion permeability of gap junction channels formed by the mutant GJB2 protein." PMID: 16217030; SCV001434014: Functional studies showed that V95M mutant formed functional channels that were permeable to fluorescent tracers in transfected N2A cells and conductance measure similar to WT-Cx26. However, reduce permeability to larger molecules was demonstrated (PMID: 12562518, 16217030).; SCV005366389: Functional studies found this variant does not affect gap junction formation or ionic permeability, but does reduce the intercellular exchange of larger molecules (Wang et al. 2003. PubMed ID: 12562518; Zhang et al. 2005. PubMed ID: 16217030).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 11 pathogenic, 0 benign (OR vs. background: 115.0).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000215 — borderline rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.012) — PM2 supporting.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.V95A: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 496217); Other variants at the same amino acid residue (not pathogenic): p.V95L: VUS-low (ClinVar VariationId 4856990, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (20/20 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_004004.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	GJB2 NM_004004.6	MANE Select	c.283G>A p.Val95Met	missense	Exon 2 of 2	Prot: NP_003995.2

GJB2 NM_004004.6

MANE Select

HGVSc / HGVSpc.283G>Ap.Val95Met

Exon rankExon 2 of 2

missense

Prot: NP_003995.2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	GJB2 ENST00000382848.5	TSL:1MANE Select	c.283G>A p.Val95Met	missense	Exon 2 of 2	Prot: ENSP00000372299.4 UniProt:
	GJB2 ENST00000382844.2	TSL:6	c.283G>A p.Val95Met	missense	Exon 1 of 1	Prot: ENSP00000372295.1 UniProt:
	GJB2 ENST00000906230.1		c.283G>A p.Val95Met	missense	Exon 2 of 2	Prot: ENSP00000576289.1 UniProt:

GJB2 ENST00000382848.5

TSL:1MANE Select

HGVSc / HGVSpc.283G>Ap.Val95Met

Exon rankExon 2 of 2

missense

Prot: ENSP00000372299.4UniProt: P29033

GJB2 ENST00000382844.2

TSL:6

HGVSc / HGVSpc.283G>Ap.Val95Met

Exon rankExon 1 of 1

missense

Prot: ENSP00000372295.1UniProt: P29033

GJB2 ENST00000906230.1

HGVSc / HGVSpc.283G>Ap.Val95Met

Exon rankExon 2 of 2

missense

Prot: ENSP00000576289.1UniProt: P29033

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000788	AC:12	Hom:0	AN:152194	Cov:33
GnomAD2 exomes	AF: 0.0000478	AC:12	Hom:	AN:251118	Cov:
GnomAD4 exome	AF: 0.0000452	AC:66	Hom:0	AN:1461678	Cov:33
GnomAD4 genome	AF: 0.0000788	AC:12	Hom:0	AN:152314	Cov:33
TOPMed (Bravo)	AF: 0.0000416	AC:11	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000564	AC:20	Hom:0	AN:354820	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000104 *	1	9622	0.00 *	0	10428
Epi25(Epilepsy)	0.00	0	41958	0.0000449	3	66888
SCHEMA(Schizophrenia)	0.0000447	5	111944	0.0000380	7	184316

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (7)
6	-	-	Autosomal recessive nonsyndromic hearing loss 1A (6)
1	-	-	Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1844678:X-linked mixed hearing loss with perilymphatic gusher;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A (1)
1	-	-	Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A (1)
1	-	-	GJB2-related disorder (1)
1	-	-	Hearing impairment (1)
1	-	-	Nonsyndromic Deafness (1)
1	-	-	Nonsyndromic genetic hearing loss (1)
1	-	-	Rare genetic deafness (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	27
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.92	D
GPN-Star LLR	N/A	-7.9
GPN-Star score	N/A	7.9
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	3/97	disease causing (ClinVar)
MutationAssessor	Pathogenic	3.1	M
PhyloP100	Benign	2.2
popEVE	Benign	-3.2
PrimateAI	Uncertain	0.69	T
PromoterAI	N/A	0.030	Neutral
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.024	D
Varity_R	N/A	0.66
VESM-3B	Benign	-7.3

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs111033299;

hg19: chr13-20763438;

COSMIC: COSV105324836;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar