13-20222745-C-T

Variant names:

• chr13-20222745-C-T
• rs781689203
• NM_001110219.3:c.736G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_001110219.3(GJB6):​c.736G>A​(p.Glu246Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,786 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: 0.000017 (0 hom.)
• Consequence: GJB6 NM_001110219.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.45

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_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1321891).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000171 (25/1461786) while in subpopulation SAS AF= 0.000232 (20/86250). AF 95% confidence interval is 0.000153. There are 0 homozygotes in gnomad4_exome. There are 18 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB6	NM_001110219.3	c.736G>A	p.Glu246Lys	missense_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.736G>A	p.Glu246Lys	missense_variant	Exon 5 of 5		NM_001110219.3	ENSP00000493834.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000278 AC: 7 AN: 251426 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135878

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.736G>A (p.E246K) alteration is located in exon 3 (coding exon 1) of the GJB6 gene. This alteration results from a G to A substitution at nucleotide position 736, causing the glutamic acid (E) at amino acid position 246 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	23
DANN	Benign	0.78
DEOGEN2	Benign	0.15	T;T;T;T;T;T;T;T;T;T;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.093
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.90	.;.;.;.;.;.;.;.;.;.;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	0.81	L;L;L;L;L;L;L;L;L;L;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.52	N;.;N;N;.;.;N;.;.;.;.
REVEL	Uncertain	0.47
Sift	Benign	0.54	T;.;T;T;.;.;T;.;.;.;.
Sift4G	Benign	0.44	T;.;T;T;.;.;T;.;.;.;.
Polyphen		0.17	B;B;B;B;B;B;B;B;B;B;B
Vest4		0.40
MutPred		0.30		Gain of ubiquitination at E246 (P = 9e-04);Gain of ubiquitination at E246 (P = 9e-04);Gain of ubiquitination at E246 (P = 9e-04);Gain of ubiquitination at E246 (P = 9e-04);Gain of ubiquitination at E246 (P = 9e-04);Gain of ubiquitination at E246 (P = 9e-04);Gain of ubiquitination at E246 (P = 9e-04);Gain of ubiquitination at E246 (P = 9e-04);Gain of ubiquitination at E246 (P = 9e-04);Gain of ubiquitination at E246 (P = 9e-04);Gain of ubiquitination at E246 (P = 9e-04);
MVP		0.90
MPC		0.11
ClinPred		0.067	T
GERP RS		5.6
Varity_R		0.19
gMVP		0.49

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: rs781689203; hg19: chr13-20796884;