13-20189571-C-T

Variant names:

• chr13-20189571-C-T
• rs111033222
• NM_004004.6:c.11G>A
• GJB2 p.Gly4Asp

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-4 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -4 classification points (ACMG Germline Pathogenicity v2019). BP6_Strong

The NM_004004.6(GJB2):c.11G>A (p.Gly4Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000231 (AC=373) in the gnomAD database across 1,614,044 control chromosomes, including 8 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0024. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars).

• Frequency:
  • Genomes: 𝑓 0.00055 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (7 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:15
• Conservation: PhyloP100: 0.410
• Publications: 23 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_benign. The variant received -4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 0 star(s). ClinVar submissions strongly and reliably favor benignity (11/12 total B/LB).

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.11G>A p.Gly4Asp	missense	Exon 2 of 2	Prot: NP_003995.2

GJB2 NM_004004.6

MANE Select

HGVSc / HGVSpc.11G>Ap.Gly4Asp

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.11G>A p.Gly4Asp	missense	Exon 2 of 2	Prot: ENSP00000372299.4 UniProt:
	GJB2 ENST00000382844.2	TSL:6	c.11G>A p.Gly4Asp	missense	Exon 1 of 1	Prot: ENSP00000372295.1 UniProt:
	GJB2 ENST00000906230.1		c.11G>A p.Gly4Asp	missense	Exon 2 of 2	Prot: ENSP00000576289.1 UniProt:

GJB2 ENST00000382848.5

TSL:1MANE Select

HGVSc / HGVSpc.11G>Ap.Gly4Asp

Exon rankExon 2 of 2

missense

Prot: ENSP00000372299.4UniProt: P29033

GJB2 ENST00000382844.2

TSL:6

HGVSc / HGVSpc.11G>Ap.Gly4Asp

Exon rankExon 1 of 1

missense

Prot: ENSP00000372295.1UniProt: P29033

GJB2 ENST00000906230.1

HGVSc / HGVSpc.11G>Ap.Gly4Asp

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: 0.000552	AC:84	Hom:1	AN:152148	Cov:33
GnomAD2 exomes	AF: 0.000437	AC:109	Hom:	AN:249290	Cov:
GnomAD4 exome	AF: 0.000198	AC:289	Hom:7	AN:1461778	Cov:32
GnomAD4 genome	AF: 0.000552	AC:84	Hom:1	AN:152266	Cov:33
TOPMed (Bravo)	AF: 0.000661	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000454	AC:129	Hom:2	AN:284210	Cov:
Local & regional cohorts 5 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.00167	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.000692	AC:9	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.00808	AC:28	Hom:	AN:3478	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000330	AC:4	Hom:0	AN:122776	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.00112	AC:10	Hom:1	AN:8960	Cov:

Showing 11 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.000286	12	41958	0.000404	27	66888
SCHEMA(Schizophrenia)	0.000610	69	113090	0.000399	76	190452

Showing 2 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
-	-	7	not provided (7)
-	1	4	not specified (5)
-	1	2	Autosomal recessive nonsyndromic hearing loss 1A (3)
-	-	1	Autosomal dominant nonsyndromic hearing loss 3A (1)
-	-	1	Ichthyosis, hystrix-like, with hearing loss (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	20
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.55	D
GPN-Star LLR	N/A	-4.4
GPN-Star score	N/A	4.4
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.69	D
Mutation Taster	N/A	96/4	polymorphism
MutationAssessor	Benign	1.4	L
PhyloP100	Benign	0.41
popEVE	Benign	-2.7
PrimateAI	Benign	0.45	T
PromoterAI	N/A	0.044	Neutral
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.36
Sift	Benign	0.059	T
Sift4G	Benign	0.27	T
Varity_R	N/A	0.42
VESM-3B	Benign	-7.2

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: rs111033222;

hg19: chr13-20763710;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar