rs373334326

Variant names:

• chrX-71224214-C-T
• rs373334326
• NM_000166.6:c.507C>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000166.6(GJB1):​c.507C>T​(p.Asp169Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,203,970 control chromosomes in the GnomAD database, including 18 homozygotes. There are 810 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00060 (2 hom., 26 hem., cov: 22)
  • Exomes 𝑓: 0.0013 (16 hom. 784 hem.)
• Consequence: GJB1 NM_000166.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.203
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-71224214-C-T is Benign according to our data. Variant chrX-71224214-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 368626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.203 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0006 (66/109961) while in subpopulation SAS AF = 0.0174 (43/2466). AF 95% confidence interval is 0.0133. There are 2 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.507C>T	p.Asp169Asp	synonymous	Exon 2 of 2	NP_000157.1	P08034
	GJB1	NM_001097642.3		c.507C>T	p.Asp169Asp	synonymous	Exon 2 of 2	NP_001091111.1	P08034
	GJB1	NM_001440770.1		c.507C>T	p.Asp169Asp	synonymous	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.507C>T	p.Asp169Asp	synonymous	Exon 2 of 2	ENSP00000354900.6	P08034
	GJB1	ENST00000374029.2	TSL:5	c.507C>T	p.Asp169Asp	synonymous	Exon 2 of 2	ENSP00000363141.1	P08034
	GJB1	ENST00000447581.2	TSL:5	c.507C>T	p.Asp169Asp	synonymous	Exon 3 of 3	ENSP00000407223.2	P08034

Frequencies

GnomAD3 genomes AF: 0.000582 AC: 64 AN: 109909 Hom.: 2 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000675

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00851

Gnomad NFE AF: 0.000228

Gnomad OTH AF: 0.00137

GnomAD2 exomes AF: 0.00241 AC: 419 AN: 174151 AF XY: 0.00394

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000223

Gnomad ASJ exome AF: 0.000549

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00133 AC: 1460 AN: 1094009 Hom.: 16 Cov.: 32 AF XY: 0.00218 AC XY: 784 AN XY: 360297

African (AFR) AF: 0.00 AC: 0 AN: 26366

American (AMR) AF: 0.000371 AC: 13 AN: 35004

Ashkenazi Jewish (ASJ) AF: 0.000518 AC: 10 AN: 19305

East Asian (EAS) AF: 0.0000663 AC: 2 AN: 30146

South Asian (SAS) AF: 0.0216 AC: 1160 AN: 53648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38345

Middle Eastern (MID) AF: 0.00677 AC: 28 AN: 4133

European-Non Finnish (NFE) AF: 0.000200 AC: 168 AN: 841060

Other (OTH) AF: 0.00172 AC: 79 AN: 46002

GnomAD4 genome AF: 0.000600 AC: 66 AN: 109961 Hom.: 2 Cov.: 22 AF XY: 0.000808 AC XY: 26 AN XY: 32189

African (AFR) AF: 0.00 AC: 0 AN: 30174

American (AMR) AF: 0.000674 AC: 7 AN: 10384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2627

East Asian (EAS) AF: 0.00 AC: 0 AN: 3459

South Asian (SAS) AF: 0.0174 AC: 43 AN: 2466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5899

Middle Eastern (MID) AF: 0.00935 AC: 2 AN: 214

European-Non Finnish (NFE) AF: 0.000228 AC: 12 AN: 52587

Other (OTH) AF: 0.00135 AC: 2 AN: 1483

Alfa AF: 0.000618 Hom.: 2

Bravo AF: 0.000276

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Charcot-Marie-Tooth disease (2)
-	-	1	Charcot-Marie-Tooth disease X-linked dominant 1 (1)
-	-	1	Charcot-Marie-Tooth Neuropathy X (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.5
DANN	Benign	0.62
PhyloP100		-0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs373334326; hg19: chrX-70444064; COSMIC: COSV62139771; COSMIC: COSV62139771;