rs1064793139

Variant names:

• chrX-71223721-G-T
• rs1064793139
• NM_000166.6:c.14G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1 PP2 BP4 BS2

The NM_000166.6(GJB1):​c.14G>T​(p.Gly5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,097,531 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. 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. G5S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000016 (0 hom. 5 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 3.30
• 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: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000166.6
• 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=0.42368376).
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6	c.14G>T	p.Gly5Val	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.14G>T	p.Gly5Val	missense_variant	Exon 2 of 2		NP_001091111.1
GJB1	NM_001440770.1	c.14G>T	p.Gly5Val	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.14G>T	p.Gly5Val	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000549 AC: 1 AN: 182125 AF XY: 0.0000149

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 18 AN: 1097531 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 5 AN XY: 362925

African (AFR) AF: 0.00 AC: 0 AN: 26394

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40327

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.0000214 AC: 18 AN: 841657

Other (OTH) AF: 0.00 AC: 0 AN: 46081

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease Pathogenic:1 Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Inherited Neuropathy Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Charcot-Marie-Tooth Neuropathy X Uncertain:1

Aug 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 5 of the GJB1 protein (p.Gly5Val). This variant is present in population databases (no rsID available, gnomAD 0.001%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with mitochondrial respiratory chain disease (PMID: 27812541). ClinVar contains an entry for this variant (Variation ID: 418234). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GJB1 protein function with a negative predictive value of 80%. 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. -

not provided Uncertain:1

May 10, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in an individual with a mitochondrial respiratory chain disease; however, segregation analysis and additional clinical information were not provided (PMID: 27812541); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27812541) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Uncertain	0.61	D;D;D;D;T;.;D
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	.;.;.;.;T;T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.42	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.72	D
MutationAssessor	Benign	0.28	N;N;N;N;.;.;N
PhyloP100		3.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.55	N;.;N;.;N;.;N
REVEL	Uncertain	0.49
Sift	Benign	0.38	T;.;T;.;T;.;T
Sift4G	Benign	0.36	T;.;T;.;T;.;T
Polyphen		0.24	B;B;B;B;.;.;B
Vest4		0.54
MVP		0.92
MPC		1.8
ClinPred		0.22	T
GERP RS		4.2
PromoterAI		-0.095	Neutral
Varity_R		0.50
gMVP		0.96
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1064793139; hg19: chrX-70443571;