rs80338939

Variant names:

• chr13-20189546-AC-A
• rs80338939
• NM_004004.6:c.35delG

Your query was ambiguous. Multiple possible variants found:

• chr13-20189546-AC-A
• chr13-20189546-AC-ACC

Variant summary

Our verdict is Pathogenic. The variant received 6 ACMG points: 14P and 8B. BA1 PS4 PVS1 PM3

This summary comes from the ClinGen Evidence Repository: The c.35delG variant in GJB2 is predicted to cause a premature stop codon in biologically-relevant-exon 2/2 that leads to a truncated or absent protein in a gene in which loss-of-function is an established 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:26445815). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMID:26969326, 25999548). The filtering allele frequency of the c.35delG variant in the GJB2 gene is 0.9% for European (Non-Finnish) chromosomes in the Genome Aggregation Database (1207/124552 with 95% CI), 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 hearing loss variants (BA1). The ClinGen Hearing Loss Expert Panel believes that the evidence for the pathogenicity of this variant for hearing loss outweighs the high allele frequency of the variant in population databases. Therefore, the BA1 code will not contribute to the overall classification. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive non-syndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PVS1, PM3_VS, PS4, BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA127023/MONDO:0019497/005

• Frequency:
  • Genomes: 𝑓 0.0063 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (34 hom.)
• Consequence: GJB2 NM_004004.6 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:99 O:3
• Conservation: PhyloP100: 7.85
• Publications: 860 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: G2P, Genomics England PanelApp
• keratoderma hereditarium mutilans

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

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

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

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, 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

ENSG00000296095 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 6 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	NM_004004.6	MANE Select	c.35delG	p.Gly12ValfsTer2	frameshift	Exon 2 of 2	NP_003995.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB2	ENST00000382848.5	TSL:1 MANE Select	c.35delG	p.Gly12ValfsTer2	frameshift	Exon 2 of 2	ENSP00000372299.4
	GJB2	ENST00000382844.2	TSL:6	c.35delG	p.Gly12ValfsTer2	frameshift	Exon 1 of 1	ENSP00000372295.1
	GJB2	ENST00000906230.1		c.35delG	p.Gly12ValfsTer2	frameshift	Exon 2 of 2	ENSP00000576289.1

Frequencies

GnomAD3 genomes AF: 0.00627 AC: 952 AN: 151764 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00124

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00584

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000833

Gnomad FIN AF: 0.00956

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00980

Gnomad OTH AF: 0.0106

GnomAD2 exomes AF: 0.00597 AC: 1488 AN: 249362 AF XY: 0.00599

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00480

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00808

Gnomad NFE exome AF: 0.00920

Gnomad OTH exome AF: 0.00718

GnomAD4 exome AF: 0.00713 AC: 10423 AN: 1461600 Hom.: 34 Cov.: 32 AF XY: 0.00701 AC XY: 5100 AN XY: 727098

African (AFR) AF: 0.00128 AC: 43 AN: 33480

American (AMR) AF: 0.00494 AC: 221 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00356 AC: 93 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000592 AC: 51 AN: 86208

European-Finnish (FIN) AF: 0.00947 AC: 506 AN: 53412

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5764

European-Non Finnish (NFE) AF: 0.00818 AC: 9092 AN: 1111824

Other (OTH) AF: 0.00652 AC: 394 AN: 60388

GnomAD4 genome AF: 0.00627 AC: 952 AN: 151882 Hom.: 4 Cov.: 32 AF XY: 0.00601 AC XY: 446 AN XY: 74244

African (AFR) AF: 0.00123 AC: 51 AN: 41382

American (AMR) AF: 0.00583 AC: 89 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5152

South Asian (SAS) AF: 0.000833 AC: 4 AN: 4800

European-Finnish (FIN) AF: 0.00956 AC: 101 AN: 10562

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00980 AC: 666 AN: 67938

Other (OTH) AF: 0.0104 AC: 22 AN: 2106

Alfa AF: 0.00556 Hom.: 0

Bravo AF: 0.00549

EpiCase AF: 0.00916

EpiControl AF: 0.00842

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
38	-	-	Autosomal recessive nonsyndromic hearing loss 1A (39)
20	-	-	not provided (20)
7	-	-	Hearing impairment (7)
4	-	-	Autosomal dominant nonsyndromic hearing loss 3A (4)
4	-	-	GJB2-related disorder (4)
4	-	-	Hearing loss, autosomal recessive (5)
3	-	-	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 (4)
2	-	-	Knuckle pads, deafness AND leukonychia syndrome (2)
2	-	-	Nonsyndromic genetic hearing loss (2)
1	-	-	Autosomal recessive nonsyndromic hearing loss 104 (1)
1	-	-	Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B (1)
1	-	-	Bilateral conductive hearing impairment;C1384666:Hearing impairment (1)
1	-	-	Bilateral sensorineural hearing impairment (1)
1	-	-	Bilateral sensorineural hearing impairment;C1384666:Hearing impairment (1)
1	-	-	Deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=5/195	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: rs80338939; hg19: chr13-20763685; COSMIC: COSV101241530; COSMIC: COSV101241530;