rs397517206

Positions:

• chr13-20223419-CCG-CA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001110219.3(GJB6):​c.60_61delinsT​(p.Lys22ArgfsTer13) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJB6 NM_001110219.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.96

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 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 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB6	NM_001110219.3	c.60_61delinsT	p.Lys22ArgfsTer13	frameshift_variant	5/5	ENST00000647029.1	NP_001103689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB6	ENST00000647029.1	c.60_61delinsT	p.Lys22ArgfsTer13	frameshift_variant	5/5		NM_001110219.3	ENSP00000493834	P1

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 21, 2018

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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2023

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397517206; hg19: chr13-20797559;