chr13-20222745-C-G

Variant names:

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

Variant summary

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

The NM_001110219.3(GJB6):​c.736G>C​(p.Glu246Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GJB6 NM_001110219.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 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=0.18620646).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB6	NM_001110219.3	c.736G>C	p.Glu246Gln	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>C	p.Glu246Gln	missense_variant	Exon 5 of 5		NM_001110219.3	ENSP00000493834.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251426 Hom.: 0 AF XY: 0.00 AC XY: 0 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461786 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 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: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Benign	0.64
DEOGEN2	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.013
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	.;.;.;.;.;.;.;.;.;.;D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	0.81	L;L;L;L;L;L;L;L;L;L;L
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.18	N;.;N;N;.;.;N;.;.;.;.
REVEL	Uncertain	0.42
Sift	Benign	0.40	T;.;T;T;.;.;T;.;.;.;.
Sift4G	Benign	0.58	T;.;T;T;.;.;T;.;.;.;.
Polyphen		0.20	B;B;B;B;B;B;B;B;B;B;B
Vest4		0.35
MutPred		0.16		Gain of relative solvent accessibility (P = 0.1684);Gain of relative solvent accessibility (P = 0.1684);Gain of relative solvent accessibility (P = 0.1684);Gain of relative solvent accessibility (P = 0.1684);Gain of relative solvent accessibility (P = 0.1684);Gain of relative solvent accessibility (P = 0.1684);Gain of relative solvent accessibility (P = 0.1684);Gain of relative solvent accessibility (P = 0.1684);Gain of relative solvent accessibility (P = 0.1684);Gain of relative solvent accessibility (P = 0.1684);Gain of relative solvent accessibility (P = 0.1684);
MVP		0.91
MPC		0.10
ClinPred		0.20	T
GERP RS		5.6
Varity_R		0.13
gMVP		0.40

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;