13-20222793-T-A

Variant names:

• chr13-20222793-T-A
• NM_001110219.3:c.688A>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.688A>T​(p.Asn230Tyr) 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. 14/21 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: 0.362

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=0.09446317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB6	NM_001110219.3	c.688A>T	p.Asn230Tyr	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.688A>T	p.Asn230Tyr	missense_variant	Exon 5 of 5		NM_001110219.3	ENSP00000493834.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Feb 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.688A>T (p.N230Y) alteration is located in exon 3 (coding exon 1) of the GJB6 gene. This alteration results from a A to T substitution at nucleotide position 688, causing the asparagine (N) at amino acid position 230 to be replaced by a tyrosine (Y). 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	0.064
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	9.5
DANN	Benign	0.66
DEOGEN2	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.64	.;.;.;.;.;.;.;.;.;.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.094	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.074	D
MutationAssessor	Benign	-0.20	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N;.;N;N;.;.;N;.;.;.;.
REVEL	Benign	0.18
Sift	Benign	0.049	D;.;D;D;.;.;D;.;.;.;.
Sift4G	Benign	0.21	T;.;T;T;.;.;T;.;.;.;.
Polyphen		0.024	B;B;B;B;B;B;B;B;B;B;B
Vest4		0.10
MutPred		0.33		Loss of methylation at K229 (P = 0.0748);Loss of methylation at K229 (P = 0.0748);Loss of methylation at K229 (P = 0.0748);Loss of methylation at K229 (P = 0.0748);Loss of methylation at K229 (P = 0.0748);Loss of methylation at K229 (P = 0.0748);Loss of methylation at K229 (P = 0.0748);Loss of methylation at K229 (P = 0.0748);Loss of methylation at K229 (P = 0.0748);Loss of methylation at K229 (P = 0.0748);Loss of methylation at K229 (P = 0.0748);
MVP		0.81
MPC		0.12
ClinPred		0.16	T
GERP RS		3.2
Varity_R		0.053
gMVP		0.34

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: chr13-20796932;