13-20222791-AT-ATT

Position:

chr13-20222791-AT-ATT

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 6P and 5B. PVS1_StrongPM2BP6BS1

The NM_001110219.3(GJB6):c.689_690insA(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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:1

Conservation

PhyloP100: 2.50

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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.

PM2

Very rare variant in population databases, with high coverage;

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 id is 95435.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000649 (948/1461700) while in subpopulation NFE AF= 0.000815 (906/1111842). AF 95% confidence interval is 0.00077. There are 0 homozygotes in gnomad4_exome. There are 434 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB6	NM_001110219.3 linkuse as main transcript	c.689_690insA	p.Asn230LysfsTer11	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 linkuse as main transcript	c.689_690insA	p.Asn230LysfsTer11	frameshift_variant	5/5		NM_001110219.3	ENSP00000493834	P1

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000302

AC:

AN:

251346

Hom.:

AF XY:

0.000302

AC XY:

AN XY:

135834

show subpopulations

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 SAS exome

AF:

0.00

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.:

Cov.:

AF XY:

0.000597

AC XY:

434

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000815

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.000342

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.000310

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.0000966

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000559

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000531

Hom.:

Bravo

AF:

0.000370

EpiCase

AF:

0.000654

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign:1

Pathogenic, no assertion criteria provided	clinical testing	Eurofins Ntd Llc (ga)	May 20, 2013	Frameshift mutation is of a type predicted to cause disease. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2022	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) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 06, 2014

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 01, 2024

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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over