rs116840822

Positions:

• chrX-71224243-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000166.6(GJB1):​c.536G>A​(p.Cys179Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 U:1 O:1
• Conservation: PhyloP100: 10.0

Genes affected

GJB1 (HGNC:4283): (gap junction protein beta 1) This gene encodes a member of the gap junction protein family. The gap junction proteins are membrane-spanning proteins that assemble to form gap junction channels that facilitate the transfer of ions and small molecules between cells. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene cause X-linked Charcot-Marie-Tooth disease, an inherited peripheral neuropathy. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a chain Gap junction beta-1 protein (size 282) in uniprot entity CXB1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000166.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-71224243-G-A is Pathogenic according to our data. Variant chrX-71224243-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21085.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71224243-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB1	NM_000166.6	c.536G>A	p.Cys179Tyr	missense_variant	2/2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.536G>A	p.Cys179Tyr	missense_variant	2/2		NP_001091111.1
GJB1	XM_011530907.3	c.536G>A	p.Cys179Tyr	missense_variant	2/2		XP_011529209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.536G>A	p.Cys179Tyr	missense_variant	2/2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 21

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 21, 2016

The C179Y variant in the GJB1 gene has been reported previously in association with Charcot-Marie-Tooth type X1 disease (CMTX1) (Casasnovas et al., 2006). The C179Y variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C179Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size, and/or other properties. This substitution occurs at a position that is conserved across species. Different missense variants in the same codon (C179G/R) as well as multiple missense variants in nearby residues have been reported in the Human Gene Mutation Database in association with GJB1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. This variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Charcot-Marie-Tooth disease Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

-

- -

Charcot-Marie-Tooth disease X-linked dominant 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.83
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;D;D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	.;.;.;.;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.2	H;H;H;H;H
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-11	D;.;D;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;D;.;D
Sift4G	Pathogenic	0.0	D;.;D;.;D
Polyphen		1.0	D;D;D;D;D
Vest4		0.99
MutPred		0.93		Gain of phosphorylation at C179 (P = 0.0767);Gain of phosphorylation at C179 (P = 0.0767);Gain of phosphorylation at C179 (P = 0.0767);Gain of phosphorylation at C179 (P = 0.0767);Gain of phosphorylation at C179 (P = 0.0767);
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0

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: rs116840822; hg19: chrX-70444093;