rs587783647

Variant names:

• chr13-20188931-ATATC-A
• rs587783647
• NM_004004.6:c.647_650delGATA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_004004.6(GJB2):​c.647_650delGATA​(p.Arg216IlefsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,444 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R216R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: GJB2 NM_004004.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 2.24
• Publications: 6 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 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0499 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PP5: Variant 13-20188931-ATATC-A is Pathogenic according to our data. Variant chr13-20188931-ATATC-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 158609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB2	NM_004004.6	c.647_650delGATA	p.Arg216IlefsTer17	frameshift_variant	Exon 2 of 2	ENST00000382848.5	NP_003995.2
GJB2	XM_011535049.3	c.647_650delGATA	p.Arg216IlefsTer17	frameshift_variant	Exon 2 of 2		XP_011533351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB2	ENST00000382848.5	c.647_650delGATA	p.Arg216IlefsTer17	frameshift_variant	Exon 2 of 2	1	NM_004004.6	ENSP00000372299.4
GJB2	ENST00000382844.2	c.647_650delGATA	p.Arg216IlefsTer17	frameshift_variant	Exon 1 of 1	6		ENSP00000372295.1
ENSG00000296095	ENST00000736390.1	n.232-3355_232-3352delGATA		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000481 AC: 12 AN: 249266 AF XY: 0.0000370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461240 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 726916

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52846

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111948

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.000196 AC: 3 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Mar 11, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein elongation, as the last 11 amino acids are replaced with 16 different amino acids.; This variant is associated with the following publications: (PMID: 15365987, 17041943, 11102979, 25288386, 31160754, 17666888) -

Jun 25, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 18, 2024

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity. (http://gnomad.broadinstitute.org) This variant has been identified in at least one individual with clinical features associated with this gene. In some published literature, this variant is referred to as 645-648delTAGA. This variant is expected to extend the open reading frame, and is therefore not expected to cause loss of protein expression through nonsense-mediated decay. However, it may still disrupt protein function. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -

Jun 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg216Ilefs*17) in the GJB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 11 amino acid(s) of the GJB2 protein. This variant is present in population databases (rs587783647, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with autosomal recessive sensorineural deafness (PMID: 11102979, 17041943, 17666888, 25288386). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.645-648delTAGA. ClinVar contains an entry for this variant (Variation ID: 158609). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

Dec 21, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GJB2 c.647_650delGATA; p.Arg216IlefsTer17 variant (rs587783647), also known as c.645_648delTAGA, is reported in the literature in the compound heterozygous state in multiple individuals affected with autosomal-recessive nonsyndromic hearing loss (Azaiez 2004, Hernandez-Juarez 2014, Prasad 2000, Putcha 2007, Tang 2006). This variant is reported as pathogenic or likely pathogenic by multiple laboratories in ClinVar (Variation ID: 158609), and is found in the Latino population with an allele frequency of 0.035% (12/34560 alleles) in the Genome Aggregation Database. This variant results in a premature termination codon in the last exon of the GJB2 gene. While this may not lead to nonsense-mediated decay, it is expected to create an altered protein that would include a sequence of 17 amino acid residues not usually present. Furthermore, functional analyses show that small deletions or additions to the C-terminus of the protein affect channel function (Locke 2011). Based on available information, this variant is considered to be pathogenic. References: Azaiez H et al. GJB2: the spectrum of deafness-causing allele variants and their phenotype. Hum Mutat. 2004 Oct;24(4):305-11. Hernandez-Juarez AA et al. GJB2 and GJB6 mutations are an infrequent cause of autosomal-recessive nonsyndromic hearing loss in residents of Mexico. Int J Pediatr Otorhinolaryngol. 2014 Dec;78(12):2107-12. Locke D et al. Mechanism for modulation of gating of connexin26-containing channels by taurine. J Gen Physiol. 2011 Sep;138(3):321-39. Prasad S et al. Genetic testing for hereditary hearing loss: connexin 26 (GJB2) allele variants and two novel deafness-causing mutations (R32C and 645-648delTAGA). Hum Mutat. 2000 Dec;16(6):502-8. Putcha GV et al. A multicenter study of the frequency and distribution of GJB2 and GJB6 mutations in a large North American cohort. Genet Med. 2007 Jul;9(7):413-26. Tang HY et al. DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls. Am J Med Genet A. 2006 Nov 15;140(22):2401-15. -

Autosomal recessive nonsyndromic hearing loss 1A Pathogenic:3

Jan 09, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GJB2 c.647_650delGATA (p.Arg216IlefsX17) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 4.8e-05 in 250054 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Autosomal Recessive Non-Syndromic Hearing Loss (4.8e-05 vs 0.025), allowing no conclusion about variant significance. c.647_650delGATA has been reported in the literature in multiple individuals affected with Autosomal Recessive Non-Syndromic Hearing Loss (examples: Prasad_2000, Tang_2006, Putcha_2007). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11102979, 17666888, 17041943). ClinVar contains an entry for this variant (Variation ID: 158609). Based on the evidence outlined above, the variant was classified as pathogenic. -

May 09, 2017

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 21, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Inborn genetic diseases Pathogenic:1

May 14, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration occurs at the 3' terminus of the GJB2 gene, is not expected to trigger nonsense-mediated mRNA decay and results in the elongation of the protein by 5 amino acids. This frameshift impacts the last 17 amino acids of the native protein. However, frameshifts are typically deleterious in nature. for autosomal recessive non-syndromic hearing loss; however, it is unlikely to be causative of autosomal dominant non-syndromic hearing loss or syndromic hearing loss with ectodermal involvement. Based on data from gnomAD, this allele has an overall frequency of 0.005% (12/249266) total alleles studied. The highest observed frequency was 0.035% (12/34560) of Latino alleles. This variant has been identified in the homozygous state and/or in conjunction with other GJB2 variants in individuals with features consistent with GJB2-related nonsyndromic hearing loss; in at least one instance, the variants were identified in trans (Prasad, 2000; Azaiez, 2004; Tang, 2006; Hernández-Juárez, 2014; Ambry internal data). Based on the available evidence, this alteration is classified as pathogenic. -

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 Pathogenic:1

Feb 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hearing impairment Pathogenic:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rare genetic deafness Pathogenic:1

Aug 05, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg216fs variant in GJB2 has been previously reported in at least 8 individuals with hearing loss, at least 4 of which were compound heterozygous for a second pathogenic variant in GJB2 (Prasad 2000 PMID: 11102979, Tang 2006 PMID: 17041943, Putcha 2007 PMID: 17666888, Hernandez-Juarez 2014 PMID: 25288386). This variant has also been reported as c.645_648delTAGA in the literature. It has also been identified in 0.03% (12/34560) of Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 158609). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 216 and leads to a new termination codon 17 amino acids downstream, thus resulting in a longer protein (the abnormal protein is 5 amino acids longer than the normal protein). This variant is expected to disrupt the normal function of the protein; however additional data is needed to confirm this. In summary, the p.Arg216fs variant is pathogenic for autosomal recessive nonsyndromic hearing loss. ACMG/AMP Criteria applied: PM3_Very Strong, PM4, PM2_Supporting. -

Autosomal dominant nonsyndromic hearing loss 3A Pathogenic:1

Jun 21, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

GJB2-related disorder Pathogenic:1

Mar 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GJB2 c.647_650delGATA variant is predicted to result in a frameshift and premature protein termination (p.Arg216Ilefs*17). This variant has been reported as causative for autosomal recessive deafness (also described as c.645_648delGATA; Prasad et al 2000. PubMed ID: 11102979; Azaiez et al 2004. PubMed ID: 15365987; Putcha et al 2007. PubMed ID: 17666888). This variant is reported in 0.035% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in GJB2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=4/196	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: rs587783647; hg19: chr13-20763070;