chr13-20223420-CG-A

Variant names:

• chr13-20223420-CG-A
• rs397517206
• NM_001110219.3:c.60_61delCGinsT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001110219.3(GJB6):​c.60_61delCGinsT​(p.Gly21ArgfsTer13) variant causes a frameshift, missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I20I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJB6 NM_001110219.3 frameshift, missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.96
• Publications: 0 publications found

Genes affected

GJB6 (HGNC:4288): (gap junction protein beta 6) Gap junctions allow the transport of ions and metabolites between the cytoplasm of adjacent cells. They are formed by two hemichannels, made up of six connexin proteins assembled in groups. Each connexin protein has four transmembrane segments, two extracellular loops, a cytoplasmic loop formed between the two inner transmembrane segments, and the N- and C-terminus both being in the cytoplasm. The specificity of the gap junction is determined by which connexin proteins comprise the hemichannel. In the past, connexin protein names were based on their molecular weight, however the new nomenclature uses sequential numbers based on which form (alpha or beta) of the gap junction is present. This gene encodes one of the connexin proteins. Mutations in this gene have been found in some forms of deafness and in some families with hidrotic ectodermal dysplasia. [provided by RefSeq, Jul 2008]

GJB6 Gene-Disease associations (from GenCC):

• Clouston syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, ClinGen, G2P, Orphanet, 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
• autosomal dominant nonsyndromic hearing loss 3B

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive nonsyndromic hearing loss 1B

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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. There are 9 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB6	NM_001110219.3	c.60_61delCGinsT	p.Gly21ArgfsTer13	frameshift_variant, missense_variant	Exon 5 of 5	ENST00000647029.1	NP_001103689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB6	ENST00000647029.1	c.60_61delCGinsT	p.Gly21ArgfsTer13	frameshift_variant, missense_variant	Exon 5 of 5		NM_001110219.3	ENSP00000493834.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Jun 13, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GJB6 c.60_61delinsT (p.Lys22ArgfsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, however current evidence is not sufficient to establish loss of function as a mechanism for disease. The variant was absent in 1614078 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.60_61delinsT in individuals affected with Hidrotic Ectodermal Dysplasia Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 45506). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Feb 21, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Lys22ArgfsX13 variant in GJB6 has not been reported in the literature but wa s submitted to ClinVar by GeneDx (ClinVar Variation ID: 45506). This variant may be represented in the Genome Aggregation Database as two variants (a frameshift and a single nucleotide variant) which have been reported in that database at i dentical frequencies and are likely in cis, with the highest frequency of 0.04% (56/126616) in European chromosomes (gnomAD, http://gnomad.broadinstitute.org; d bSNP rs199552278 and rs778513540). This variant is predicted to cause a frameshi ft, which alters the protein's amino acid sequence beginning at codon 22 and lea ds to a premature stop codon 13 codons downstream. This alteration is then predi cted to lead to a truncated or absent protein. However, the role of GJB6 loss of function (LOF) variants in nonsyndromic hearing loss or any phenotype is curren tly unknown. Certain missense variants in GJB6 have previously been associated w ith autosomal dominant hidrotic ectodermal dysplasia (Clouston syndrome) (Lamart ine 2000). However, the only recessive GJB6 variants with sufficient evidence fo r pathogenicity are large deletions that likely delete regulatory elements contr olling GJB2 expression. This is consistent with other overlapping pathogenic del etions that do not impact GJB6 coding sequencing. In summary, it's unknown what phenotype, if any, might be associated with either heterozygous or biallelic los s of function sequence variants in GJB6 and as such, this variant is classified as uncertain significance. ACMG/AMP Criteria applied: None. -

not provided Uncertain:1

Oct 16, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation as the last 240 amino acids are replaced with 12 different amino acids; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0

Splicing

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

Other links and lift over

dbSNP: rs397517206; hg19: chr13-20797559;