rs111033299

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr13-20189299-C-T
• chr13-20189299-C-A
• chr13-20189299-C-G

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM5 PP2 PP3_Strong PP5_Very_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 frequency of 0.0000483 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V95A) has been classified as Likely pathogenic. The gene GJB2 is included in the ClinGen Criteria Specification Registry.

• 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:18
• Conservation: PhyloP100: 2.15
• 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. 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. The gap junction proteins, also known as connexins, purified from fractions of enriched gap junctions from different tissues differ. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Oct 2008]

GJB2 Gene-Disease associations (from GenCC):

• Bart-Pumphrey syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• ichthyosis, hystrix-like, with hearing loss

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

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

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• syndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• 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: Ambry Genetics, Genomics England PanelApp
• autosomal dominant nonsyndromic hearing loss 3A

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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:):

ACMG classification

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

Our verdict: Pathogenic. The variant received 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: 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).
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_004004.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-20189298-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 496217.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 111 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: -0.72044 (below the threshold of 3.09). Trascript score misZ: 0.4379 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant nonsyndromic hearing loss 3A, ichthyosis, hystrix-like, with hearing loss, autosomal recessive nonsyndromic hearing loss 1A, nonsyndromic genetic hearing loss, palmoplantar keratoderma-deafness syndrome, keratoderma hereditarium mutilans, Bart-Pumphrey syndrome, KID syndrome, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, autosomal dominant nonsyndromic hearing loss, hearing loss, autosomal recessive, syndromic genetic hearing loss.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 13-20189299-C-T is Pathogenic according to our data. Variant chr13-20189299-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 44735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004004.6. You can select a different transcript below to see updated ACMG 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	NP_003995.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	ENST00000382848.5	TSL:1 MANE Select	c.283G>A	p.Val95Met	missense	Exon 2 of 2	ENSP00000372299.4	P29033
	GJB2	ENST00000382844.2	TSL:6	c.283G>A	p.Val95Met	missense	Exon 1 of 1	ENSP00000372295.1	P29033
	GJB2	ENST00000906230.1		c.283G>A	p.Val95Met	missense	Exon 2 of 2	ENSP00000576289.1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000478 AC: 12 AN: 251118 AF XY: 0.0000663

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000452 AC: 66 AN: 1461678 Hom.: 0 Cov.: 33 AF XY: 0.0000578 AC XY: 42 AN XY: 727146

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1112002

Other (OTH) AF: 0.0000497 AC: 3 AN: 60392

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74482

African (AFR) AF: 0.0000481 AC: 2 AN: 41574

American (AMR) AF: 0.000458 AC: 7 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000543 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
5	-	-	Autosomal recessive nonsyndromic hearing loss 1A (5)
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

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
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
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		2.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.93		Gain of disorder (P = 0.0826)
MVP		0.97
MPC		0.26
ClinPred		0.65	D
GERP RS		4.2
PromoterAI		0.030	Neutral
Varity_R		0.66
gMVP		0.94
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs111033299; hg19: chr13-20763438; COSMIC: COSV105324836;