X-71223855-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000166.6(GJB1):c.148T>G(p.Ser50Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000898 in 111,308 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. S50P) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 23)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.84

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000166.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-71223855-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 430122.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.148T>G	p.Ser50Ala	missense_variant	2/2	ENST00000361726.7
GJB1	NM_001097642.3	c.148T>G	p.Ser50Ala	missense_variant	2/2
GJB1	XM_011530907.3	c.148T>G	p.Ser50Ala	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.148T>G	p.Ser50Ala	missense_variant	2/2	1	NM_000166.6	P1

Frequencies

GnomAD3 genomes AF: 0.00000898 AC: 1 AN: 111308 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33522

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000958

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000898 AC: 1 AN: 111308 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33522

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000958

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth Neuropathy X Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 22, 2022

This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 50 of the GJB1 protein (p.Ser50Ala). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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	0.097
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	21
Dann	Benign	0.91
DEOGEN2	Pathogenic	0.82	D;D;D;D;T;.;D
FATHMM_MKL	Benign	0.71	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	0.0	N;N;N;N;.;.;N
MutationTaster	Benign	0.73	N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.6	N;.;N;.;N;.;N
REVEL	Uncertain	0.43
Sift	Benign	0.044	D;.;D;.;T;.;D
Sift4G	Benign	0.077	T;.;T;.;T;.;T
Polyphen		0.0010	B;B;B;B;.;.;B
Vest4		0.16
MutPred		0.55		Loss of disorder (P = 0.0617);Loss of disorder (P = 0.0617);Loss of disorder (P = 0.0617);Loss of disorder (P = 0.0617);Loss of disorder (P = 0.0617);Loss of disorder (P = 0.0617);Loss of disorder (P = 0.0617);
MVP		0.88
MPC		0.64
ClinPred		0.16	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.17
gMVP		0.90

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: rs913934445; hg19: chrX-70443705;