rs190676487

Variant names:

• chrX-71223275-G-A
• rs190676487
• NM_000166.6:c.-77G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000166.6(GJB1):​c.-77G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 237,901 control chromosomes in the GnomAD database, including 8 homozygotes. There are 158 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 0.0047 (7 hom., 138 hem., cov: 22)
  • Exomes 𝑓: 0.00072 (1 hom. 20 hem.)
• Consequence: GJB1 NM_000166.6 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.25
• 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, 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant X-71223275-G-A is Benign according to our data. Variant chrX-71223275-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 384473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00469 (523/111606) while in subpopulation AFR AF = 0.0157 (483/30731). AF 95% confidence interval is 0.0146. There are 7 homozygotes in GnomAd4. There are 138 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6	c.-77G>A		5_prime_UTR_variant	Exon 1 of 2	ENST00000361726.7	NP_000157.1
GJB1	NM_001097642.3	c.-16-417G>A		intron_variant	Intron 1 of 1		NP_001091111.1
GJB1	NM_001440770.1	c.-16-417G>A		intron_variant	Intron 2 of 2		NP_001427699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7	c.-77G>A		5_prime_UTR_variant	Exon 1 of 2	1	NM_000166.6	ENSP00000354900.6

Frequencies

GnomAD3 genomes AF: 0.00464 AC: 518 AN: 111554 Hom.: 7 Cov.: 22

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

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: 0.000264

Gnomad OTH AF: 0.00267

GnomAD4 exome AF: 0.000721 AC: 91 AN: 126295 Hom.: 1 Cov.: 0 AF XY: 0.000567 AC XY: 20 AN XY: 35283

African (AFR) AF: 0.0158 AC: 72 AN: 4566

American (AMR) AF: 0.000740 AC: 5 AN: 6761

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3372

East Asian (EAS) AF: 0.00 AC: 0 AN: 6617

South Asian (SAS) AF: 0.0000728 AC: 1 AN: 13731

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6476

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 478

European-Non Finnish (NFE) AF: 0.000117 AC: 9 AN: 77170

Other (OTH) AF: 0.000561 AC: 4 AN: 7124

GnomAD4 genome AF: 0.00469 AC: 523 AN: 111606 Hom.: 7 Cov.: 22 AF XY: 0.00408 AC XY: 138 AN XY: 33794

African (AFR) AF: 0.0157 AC: 483 AN: 30731

American (AMR) AF: 0.00209 AC: 22 AN: 10509

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3529

South Asian (SAS) AF: 0.00 AC: 0 AN: 2659

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6079

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.000264 AC: 14 AN: 53044

Other (OTH) AF: 0.00264 AC: 4 AN: 1515

Alfa AF: 0.00463 Hom.: 13

Bravo AF: 0.00530

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Dec 22, 2016

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 17, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.83
PhyloP100		1.3
PromoterAI		-0.0030	Neutral
Mutation Taster		=100/0	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: rs190676487; hg19: chrX-70443125;