X-71224497-C-A

Variant names:

• chrX-71224497-C-A
• rs587777879
• NM_000166.6:c.790C>A

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.790C>A​(p.Arg264Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000092 in 1,086,543 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts 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. R264C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.61
• 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, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• 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 X-linked progressive cerebellar ataxia, Charcot-Marie-Tooth disease X-linked dominant 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22188187).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000166.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	NM_000166.6	MANE Select	c.790C>A	p.Arg264Ser	missense	Exon 2 of 2	NP_000157.1	P08034
	GJB1	NM_001097642.3		c.790C>A	p.Arg264Ser	missense	Exon 2 of 2	NP_001091111.1	P08034
	GJB1	NM_001440770.1		c.790C>A	p.Arg264Ser	missense	Exon 3 of 3	NP_001427699.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	ENST00000361726.7	TSL:1 MANE Select	c.790C>A	p.Arg264Ser	missense	Exon 2 of 2	ENSP00000354900.6	P08034
	GJB1	ENST00000374029.2	TSL:5	c.790C>A	p.Arg264Ser	missense	Exon 2 of 2	ENSP00000363141.1	P08034
	GJB1	ENST00000447581.2	TSL:5	c.790C>A	p.Arg264Ser	missense	Exon 3 of 3	ENSP00000407223.2	P08034

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.20e-7 AC: 1 AN: 1086543 Hom.: 0 Cov.: 31 AF XY: 0.00000283 AC XY: 1 AN XY: 353907

African (AFR) AF: 0.00 AC: 0 AN: 26146

American (AMR) AF: 0.00 AC: 0 AN: 34110

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19158

East Asian (EAS) AF: 0.00 AC: 0 AN: 29785

South Asian (SAS) AF: 0.0000190 AC: 1 AN: 52564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4120

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 835680

Other (OTH) AF: 0.00 AC: 0 AN: 45680

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	0.34	N
PhyloP100		2.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.19	N
REVEL	Uncertain	0.48
Sift	Benign	0.64	T
Sift4G	Benign	0.14	T
Polyphen		0.0050	B
Vest4		0.44
MutPred		0.30		Gain of phosphorylation at R264 (P = 0.0197)
MVP		0.99
MPC		0.87
ClinPred		0.42	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.76
Mutation Taster		=39/61	disease causing

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: rs587777879; hg19: chrX-70444347;