rs587781246

Variant names:

• chrX-71224395-C-G
• rs587781246
• NM_000166.6:c.688C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-71224395-C-G
• chrX-71224395-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_000166.6(GJB1):​c.688C>G​(p.Arg230Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000897 in 111,543 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R230L) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 0 hem., cov: 22)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• Publications: 15 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 3 ACMG points.

• PM1: In a chain Gap junction beta-1 protein (size 282) in uniprot entity CXB1_HUMAN there are 184 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=0.14865056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6	c.688C>G	p.Arg230Gly	missense_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.688C>G	p.Arg230Gly	missense_variant	Exon 2 of 2		NP_001091111.1
GJB1	NM_001440770.1	c.688C>G	p.Arg230Gly	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.688C>G	p.Arg230Gly	missense_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes AF: 0.00000897 AC: 1 AN: 111543 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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.: 32

GnomAD4 genome AF: 0.00000897 AC: 1 AN: 111543 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33695

African (AFR) AF: 0.0000326 AC: 1 AN: 30643

American (AMR) AF: 0.00 AC: 0 AN: 10531

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3539

South Asian (SAS) AF: 0.00 AC: 0 AN: 2638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6068

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53070

Other (OTH) AF: 0.00 AC: 0 AN: 1496

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.25	T;T;T;T;T
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.75	.;.;.;.;T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	-0.20	N;N;N;N;N
PhyloP100		1.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.68	N;.;N;.;N
REVEL	Uncertain	0.34
Sift	Benign	0.31	T;.;T;.;T
Sift4G	Benign	0.43	T;.;T;.;T
Polyphen		0.0010	B;B;B;B;B
Vest4		0.14
MutPred		0.43		Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);Loss of MoRF binding (P = 0.0131);
MVP		0.58
MPC		0.98
ClinPred		0.10	T
GERP RS		4.0
Varity_R		0.21
gMVP		0.82
Mutation Taster		=71/29	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: rs587781246; hg19: chrX-70444245;