chr13-20189095-T-C

Variant names:

• chr13-20189095-T-C
• rs80338949
• NM_004004.6:c.487A>G
• GJB2 p.Met163Val

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+9 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 9 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PP3_ModeratePP5

The NM_004004.6(GJB2):c.487A>G (p.Met163Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000929 (AC=150) in the gnomAD database across 1,614,088 control chromosomes, including 1 homozygote. The grpmax filtering allele frequency (95% CI) is 0.000721. 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 (no review stars). ClinVar reports functional evidence for this variant: "SCV004175861: Functional studies demonstrate a damaging effect on gap junction function, impacting GJB2 function (Press ER, et. al., 2017" and additional evidence is available in ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.M163L: Uncertain_significance (ClinVar VariationId 3769988, 1 star); p.M163L: Uncertain_significance (ClinVar VariationId 424854, 1 star); p.M163R: Uncertain_significance (ClinVar VariationId 1297584, 1 star); p.M163T: Uncertain_significance (ClinVar VariationId 449488, 3 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000091 (1 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:11 O:1
• Conservation: PhyloP100: 6.20
• Publications: 43 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: Likely_pathogenic. The variant received 9 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV004175861: Functional studies demonstrate a damaging effect on gap junction function, impacting GJB2 function (Press ER, et. al., 2017; Bruzzone R, et. al.,2003).
	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: 4 pathogenic, 3 benign (OR vs. background: 6.4).
	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 0-star pathogenic — supporting (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 0 star(s).

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.487A>G p.Met163Val	missense	Exon 2 of 2	Prot: NP_003995.2

GJB2 NM_004004.6

MANE Select

HGVSc / HGVSpc.487A>Gp.Met163Val

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.487A>G p.Met163Val	missense	Exon 2 of 2	Prot: ENSP00000372299.4 UniProt:
	GJB2 ENST00000382844.2	TSL:6	c.487A>G p.Met163Val	missense	Exon 1 of 1	Prot: ENSP00000372295.1 UniProt:
	GJB2 ENST00000906230.1		c.487A>G p.Met163Val	missense	Exon 2 of 2	Prot: ENSP00000576289.1 UniProt:

GJB2 ENST00000382848.5

TSL:1MANE Select

HGVSc / HGVSpc.487A>Gp.Met163Val

Exon rankExon 2 of 2

missense

Prot: ENSP00000372299.4UniProt: P29033

GJB2 ENST00000382844.2

TSL:6

HGVSc / HGVSpc.487A>Gp.Met163Val

Exon rankExon 1 of 1

missense

Prot: ENSP00000372295.1UniProt: P29033

GJB2 ENST00000906230.1

HGVSc / HGVSpc.487A>Gp.Met163Val

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: 0.000112	AC:17	Hom:0	AN:152182	Cov:33
GnomAD2 exomes	AF: 0.000143	AC:36	Hom:	AN:251140	Cov:
GnomAD4 exome	AF: 0.0000910	AC:133	Hom:1	AN:1461788	Cov:33
GnomAD4 genome	AF: 0.000112	AC:17	Hom:0	AN:152300	Cov:33
TOPMed (Bravo)	AF: 0.000159	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000762	AC:18	Hom:0	AN:236226	Cov:
Local & regional cohorts 4 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:
GenomeAsia100K	AF: 0.000289	AC:1	Hom:	AN:3478	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000160	AC:2	Hom:0	AN:122696	Cov:
Turkish Variome	AF: 0.00239	AC:16	Hom:0	AN:6708	Cov:

Showing 10 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.000141	4	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.0000715	3	41958	0.0000150	1	66888
SCHEMA(Schizophrenia)	0.000241	14	58192	0.000186	15	80476

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

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	-	not provided (5)
2	1	-	Autosomal recessive nonsyndromic hearing loss 1A (4)
1	1	-	Autosomal dominant nonsyndromic hearing loss 3A (2)
-	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	-	-	Hearing impairment (1)
-	1	-	Nonsyndromic genetic hearing loss (1)
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
GPN-Star LLR	N/A	-7.7
GPN-Star score	N/A	7.7
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.76	D
Mutation Taster	N/A	3/97	disease causing
MutationAssessor	Benign	1.2	L
PhyloP100	Uncertain	6.2
popEVE	Benign	-2.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.87
Sift	Benign	0.23	T
Sift4G	Benign	0.17	T
Varity_R	N/A	0.67
VESM-3B	Benign	-4.6

Showing 27 of 27 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: rs80338949;

hg19: chr13-20763234;

COSMIC: COSV107493878;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar