X-71224518-G-T

Variant names:

• chrX-71224518-G-T
• rs756258267
• NM_000166.6:c.811G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_000166.6(GJB1):​c.811G>T​(p.Ala271Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A271T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.28
• Publications: 0 publications found

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]

GJB1 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease X-linked dominant 1

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)
• X-linked progressive cerebellar ataxia

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a chain Gap junction beta-1 protein (size 282) in uniprot entity CXB1_HUMAN there are 182 pathogenic changes around while only 11 benign (94%) in NM_000166.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 135 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Charcot-Marie-Tooth disease X-linked dominant 1, X-linked progressive cerebellar ataxia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32131404).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6	c.811G>T	p.Ala271Ser	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.811G>T	p.Ala271Ser	missense_variant	Exon 2 of 2		NP_001091111.1
GJB1	NM_001440770.1	c.811G>T	p.Ala271Ser	missense_variant	Exon 3 of 3		NP_001427699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.811G>T	p.Ala271Ser	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth Neuropathy X Uncertain:1

Dec 31, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 271 of the GJB1 protein (p.Ala271Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GJB1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.20	T;T;T;T;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.71	.;.;.;.;T
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.32	T;T;T;T;T
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	0.0	N;N;N;N;N
PhyloP100		4.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.13	N;.;N;.;N
REVEL	Uncertain	0.41
Sift	Benign	0.61	T;.;T;.;T
Sift4G	Benign	0.40	T;.;T;.;T
Polyphen		0.96	D;D;D;D;D
Vest4		0.12
MutPred		0.23		Gain of glycosylation at A271 (P = 0.0029);Gain of glycosylation at A271 (P = 0.0029);Gain of glycosylation at A271 (P = 0.0029);Gain of glycosylation at A271 (P = 0.0029);Gain of glycosylation at A271 (P = 0.0029);
MVP		0.94
MPC		1.1
ClinPred		0.46	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.45
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs756258267; hg19: chrX-70444368;