13-20222765-C-T

Position:

• chr13-20222765-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001110219.3(GJB6):​c.716G>A​(p.Ser239Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJB6 NM_001110219.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.522

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07472253).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB6	NM_001110219.3	c.716G>A	p.Ser239Asn	missense_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.716G>A	p.Ser239Asn	missense_variant	5/5		NM_001110219.3	ENSP00000493834	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 03, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.74
DEOGEN2	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.44	.;.;.;.;.;.;.;.;.;.;T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.075	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.55	N;N;N;N;N;N;N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.63	N;.;N;N;.;.;N;.;.;.;.
REVEL	Benign	0.24
Sift	Benign	0.46	T;.;T;T;.;.;T;.;.;.;.
Sift4G	Benign	0.51	T;.;T;T;.;.;T;.;.;.;.
Polyphen		0.0020	B;B;B;B;B;B;B;B;B;B;B
Vest4		0.036
MutPred		0.25		Gain of methylation at K240 (P = 0.1195);Gain of methylation at K240 (P = 0.1195);Gain of methylation at K240 (P = 0.1195);Gain of methylation at K240 (P = 0.1195);Gain of methylation at K240 (P = 0.1195);Gain of methylation at K240 (P = 0.1195);Gain of methylation at K240 (P = 0.1195);Gain of methylation at K240 (P = 0.1195);Gain of methylation at K240 (P = 0.1195);Gain of methylation at K240 (P = 0.1195);Gain of methylation at K240 (P = 0.1195);
MVP		0.78
MPC		0.088
ClinPred		0.074	T
GERP RS		2.8
Varity_R		0.046
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-20796904;