13-20222791-A-AT

Variant names:

• chr13-20222791-A-AT
• rs398124237
• NM_001110219.3:c.689dupA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PVS1_Strong BP6 BS1

The NM_001110219.3(GJB6):​c.689dupA​(p.Asn230LysfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00062 in 1,613,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (0 hom.)
• Consequence: GJB6 NM_001110219.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:1
• Conservation: PhyloP100: 2.50
• Publications: 11 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_benign. The variant received -1 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 0.123 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BP6: Variant 13-20222791-A-AT is Benign according to our data. Variant chr13-20222791-A-AT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95435.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000342 (52/152098) while in subpopulation AMR AF = 0.000589 (9/15270). AF 95% confidence interval is 0.000418. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB6	NM_001110219.3	c.689dupA	p.Asn230LysfsTer11	frameshift_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.689dupA	p.Asn230LysfsTer11	frameshift_variant	Exon 5 of 5		NM_001110219.3	ENSP00000493834.1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.000559

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000302 AC: 76 AN: 251346 AF XY: 0.000302

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000563

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000649 AC: 948 AN: 1461700 Hom.: 0 Cov.: 31 AF XY: 0.000597 AC XY: 434 AN XY: 727132

African (AFR) AF: 0.000119 AC: 4 AN: 33476

American (AMR) AF: 0.000201 AC: 9 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

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

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

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

European-Non Finnish (NFE) AF: 0.000815 AC: 906 AN: 1111842

Other (OTH) AF: 0.000447 AC: 27 AN: 60392

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.000310 AC XY: 23 AN XY: 74292

African (AFR) AF: 0.0000966 AC: 4 AN: 41390

American (AMR) AF: 0.000589 AC: 9 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000559 AC: 38 AN: 68024

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000531 Hom.: 0

Bravo AF: 0.000370

EpiCase AF: 0.000654

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Benign:1

Feb 04, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with no other GJB6 variant in a patient with presumed autosomal recessive hearing loss, and in a patient with hearing loss attributed to neonatal meningitis in published literature (Beck et al., 2015); Frameshift variant predicted to result in protein truncation as the last 32 amino acids are lost and replaced with 10 incorrect amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 25621899, 34426522, 25214170) -

May 20, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Frameshift mutation is of a type predicted to cause disease. -

not specified Uncertain:1

May 06, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Asn230fs variant in GJB6 has been identified in at least two other individua ls, one without clinical information and one with hearing loss (ClinVar and LMM unpublished data, respectively). In addition, this variant has been identified i n 0.1% (8/8254) of European American chromosomes by the NHLBI Exome sequencing p roject (http://evs.gs.washington.edu/EVS/). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathog enic role. This variant is predicted to cause a frameshift, which alters the pro tein?s amino acid sequence beginning at position 230 and leads to a premature te rmination codon 11 amino acids downstream. This alteration may lead to a truncat ed and altered protein. However, the role of GJB6 variants in nonsyndromic heari ng loss is currently unknown. In summary, additional information is needed to de termine the clinical significance of this variant. -

Hidrotic ectodermal dysplasia syndrome;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B;C2675237:Autosomal dominant nonsyndromic hearing loss 3B Uncertain:1

Jan 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Asn230Lysfs*11) in the GJB6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 32 amino acid(s) of the GJB6 protein. This variant is present in population databases (rs398124237, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with deafness (PMID: 25214170). This variant is also known as c.682insA, c.682- 683insA. ClinVar contains an entry for this variant (Variation ID: 95435). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
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: rs398124237; hg19: chr13-20796930; COSMIC: COSV53832598; COSMIC: COSV53832598;