rs80338942

Variant names:

• chr13-20189414-CA-C
• rs80338942
• NM_004004.6:c.167delT

Variant summary

Our verdict is Pathogenic. The variant received 2 ACMG points: 10P and 8B. BA1 PVS1 PM3

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the p.Leu56ArgfsX26 variant in the GJB2 gene is 1.4% (165/10106) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org; calculated by using inverse allele frequency at https://www.cardiodb.org/allelefrequencyapp/), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive nonsyndromic hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for nonsyndromic hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. The p.Leu56ArgfsX26 variant in GJB2 is predicted to cause a premature stop codon in the only coding exon of the gene, leading to an absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID:24529908, 26096904, 24158611, 9285800, 17666888). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA172217/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.00060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (3 hom.)
• Consequence: GJB2 NM_004004.6 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:29 O:2
• Conservation: PhyloP100: 2.62
• Publications: 243 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• 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, Orphanet, G2P
• palmoplantar keratoderma-deafness syndrome

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

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

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

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

Our verdict: Pathogenic. The variant received 2 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

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.167delT	p.Leu56ArgfsTer26	frameshift	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.167delT	p.Leu56ArgfsTer26	frameshift	Exon 2 of 2	ENSP00000372299.4	P29033
	GJB2	ENST00000382844.2	TSL:6	c.167delT	p.Leu56ArgfsTer26	frameshift	Exon 1 of 1	ENSP00000372295.1	P29033
	GJB2	ENST00000906230.1		c.167delT	p.Leu56ArgfsTer26	frameshift	Exon 2 of 2	ENSP00000576289.1

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000888 AC: 223 AN: 251070 AF XY: 0.000818

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.0164

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000502 AC: 733 AN: 1460102 Hom.: 3 Cov.: 33 AF XY: 0.000464 AC XY: 337 AN XY: 725966

African (AFR) AF: 0.0000898 AC: 3 AN: 33422

American (AMR) AF: 0.000470 AC: 21 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.0166 AC: 434 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.000164 AC: 182 AN: 1110502

Other (OTH) AF: 0.00149 AC: 90 AN: 60330

GnomAD4 genome AF: 0.000598 AC: 91 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.000578 AC XY: 43 AN XY: 74352

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.000589 AC: 9 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68030

Other (OTH) AF: 0.000955 AC: 2 AN: 2094

Alfa AF: 0.00174 Hom.: 0

Bravo AF: 0.000620

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	Autosomal recessive nonsyndromic hearing loss 1A (8)
7	-	-	not provided (7)
2	-	-	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 (3)
2	-	-	GJB2-related disorder (2)
2	-	-	Nonsyndromic genetic hearing loss (2)
1	-	-	Autosomal dominant nonsyndromic hearing loss 3A (1)
1	-	-	Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B (1)
1	-	-	Hearing impairment (1)
1	-	-	Hearing loss (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Mutilating keratoderma (1)
1	-	-	Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome (1)
1	-	-	Rare genetic deafness (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=6/194	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: rs80338942; hg19: chr13-20763553;