13-20222786-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001110219.3(GJB6):c.695C>A(p.Pro232His) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GJB6 NM_001110219.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.71

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32802427).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB6	NM_001110219.3	c.695C>A	p.Pro232His	missense_variant	5/5	ENST00000647029.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB6	ENST00000647029.1	c.695C>A	p.Pro232His	missense_variant	5/5		NM_001110219.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461584 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Invitae

Aug 27, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 285797). This variant has not been reported in the literature in individuals affected with GJB6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 232 of the GJB6 protein (p.Pro232His). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 04, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	21
Dann	Benign	0.95
DEOGEN2	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Benign	0.69	N;N;N;N;N;N;N;N;N;N;N
MutationTaster	Benign	0.56	D;D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.1	N;.;N;N;.;.;N;.;.;.;.
REVEL	Uncertain	0.41
Sift	Benign	0.071	T;.;T;T;.;.;T;.;.;.;.
Sift4G	Benign	0.27	T;.;T;T;.;.;T;.;.;.;.
Polyphen		0.83	P;P;P;P;P;P;P;P;P;P;P
Vest4		0.14
MutPred		0.20		Loss of glycosylation at P232 (P = 0.0355);Loss of glycosylation at P232 (P = 0.0355);Loss of glycosylation at P232 (P = 0.0355);Loss of glycosylation at P232 (P = 0.0355);Loss of glycosylation at P232 (P = 0.0355);Loss of glycosylation at P232 (P = 0.0355);Loss of glycosylation at P232 (P = 0.0355);Loss of glycosylation at P232 (P = 0.0355);Loss of glycosylation at P232 (P = 0.0355);Loss of glycosylation at P232 (P = 0.0355);Loss of glycosylation at P232 (P = 0.0355);
MVP		0.96
MPC		0.11
ClinPred		0.54	D
GERP RS		5.6
Varity_R		0.091
gMVP		0.42

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

Other links and lift over

dbSNP: rs752253778; hg19: chr13-20796925;