rs373334326

Positions:

• chrX-71224214-C-A
• chrX-71224214-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000166.6(GJB1):​c.507C>A​(p.Asp169Glu) 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. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.203

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 Uncertain_significance. Variant got 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.13106209).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB1	NM_000166.6	c.507C>A	p.Asp169Glu	missense_variant	2/2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.507C>A	p.Asp169Glu	missense_variant	2/2		NP_001091111.1
GJB1	XM_011530907.3	c.507C>A	p.Asp169Glu	missense_variant	2/2		XP_011529209.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.507C>A	p.Asp169Glu	missense_variant	2/2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1094008 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 360296

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.0
DANN	Benign	0.83
DEOGEN2	Uncertain	0.73	D;D;D;D;D
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.75	.;.;.;.;T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.38	N;N;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.55	N;.;N;.;N
REVEL	Benign	0.19
Sift	Benign	0.46	T;.;T;.;T
Sift4G	Benign	0.55	T;.;T;.;T
Polyphen		0.0090	B;B;B;B;B
Vest4		0.078
MutPred		0.23		Gain of ubiquitination at K167 (P = 0.2244);Gain of ubiquitination at K167 (P = 0.2244);Gain of ubiquitination at K167 (P = 0.2244);Gain of ubiquitination at K167 (P = 0.2244);Gain of ubiquitination at K167 (P = 0.2244);
MVP		0.55
MPC		0.76
ClinPred		0.19	T
GERP RS		-5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.081
gMVP		0.89

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: rs373334326; hg19: chrX-70444064;