rs587781246

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 3P and 10B. PM1 PP2 BP4 BP6 BS1 BS2

The NM_000166.6(GJB1):​c.688C>T​(p.Arg230Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,208,253 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 74 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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 0.00022 (0 hom., 4 hem., cov: 22)
  • Exomes 𝑓: 0.00016 (0 hom. 70 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:6
• 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, 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: Benign. The variant received -7 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
• 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=0.2892338).
• BP6: Variant X-71224395-C-T is Benign according to our data. Variant chrX-71224395-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157521.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000224 (25/111543) while in subpopulation AMR AF = 0.000665 (7/10531). AF 95% confidence interval is 0.000312. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 4 XL gene

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.688C>T	p.Arg230Cys	missense	Exon 2 of 2	NP_000157.1	P08034
	GJB1	NM_001097642.3		c.688C>T	p.Arg230Cys	missense	Exon 2 of 2	NP_001091111.1	P08034
	GJB1	NM_001440770.1		c.688C>T	p.Arg230Cys	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.688C>T	p.Arg230Cys	missense	Exon 2 of 2	ENSP00000354900.6	P08034
	GJB1	ENST00000374029.2	TSL:5	c.688C>T	p.Arg230Cys	missense	Exon 2 of 2	ENSP00000363141.1	P08034
	GJB1	ENST00000447581.2	TSL:5	c.688C>T	p.Arg230Cys	missense	Exon 3 of 3	ENSP00000407223.2	P08034

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 25 AN: 111543 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000665

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00427

Gnomad NFE AF: 0.000264

Gnomad OTH AF: 0.00134

GnomAD2 exomes AF: 0.000112 AC: 20 AN: 179254 AF XY: 0.000171

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000728

Gnomad FIN exome AF: 0.0000675

Gnomad NFE exome AF: 0.000137

Gnomad OTH exome AF: 0.000676

GnomAD4 exome AF: 0.000163 AC: 179 AN: 1096710 Hom.: 0 Cov.: 32 AF XY: 0.000193 AC XY: 70 AN XY: 362228

African (AFR) AF: 0.00 AC: 0 AN: 26385

American (AMR) AF: 0.0000569 AC: 2 AN: 35157

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19357

East Asian (EAS) AF: 0.00 AC: 0 AN: 30167

South Asian (SAS) AF: 0.000204 AC: 11 AN: 53918

European-Finnish (FIN) AF: 0.0000251 AC: 1 AN: 39822

Middle Eastern (MID) AF: 0.000726 AC: 3 AN: 4135

European-Non Finnish (NFE) AF: 0.000181 AC: 152 AN: 841718

Other (OTH) AF: 0.000217 AC: 10 AN: 46051

GnomAD4 genome AF: 0.000224 AC: 25 AN: 111543 Hom.: 0 Cov.: 22 AF XY: 0.000119 AC XY: 4 AN XY: 33695

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

American (AMR) AF: 0.000665 AC: 7 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: 0.00427 AC: 1 AN: 234

European-Non Finnish (NFE) AF: 0.000264 AC: 14 AN: 53070

Other (OTH) AF: 0.00134 AC: 2 AN: 1496

Alfa AF: 0.0000878 Hom.: 0

Bravo AF: 0.000181

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ExAC AF: 0.000165 AC: 20

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	1	Charcot-Marie-Tooth disease (2)
-	-	2	not specified (2)
-	-	1	Charcot-Marie-Tooth disease X-linked dominant 1 (1)
-	-	1	Charcot-Marie-Tooth Neuropathy X (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	0.34	N
PhyloP100		1.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.31	N
REVEL	Uncertain	0.64
Sift	Uncertain	0.027	D
Sift4G	Benign	0.077	T
Polyphen		0.99	D
Vest4		0.090
MVP		0.99
MPC		1.3
ClinPred		0.048	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.85
Mutation Taster		=72/28	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;