rs6525485

chrX-71222995-G-AchrX-71222995-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001097642.3(GJB1):c.-16-697G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (17658 hom., 20673 hem., cov: 22)
  • Failed GnomAD Quality Control
• Consequence: GJB1 NM_001097642.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.80

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-71222995-G-A is Benign according to our data. Variant chrX-71222995-G-A is described in ClinVar as [Benign]. Clinvar id is 255410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-71222995-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 17647 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_001097642.3	c.-16-697G>A		intron_variant
GJB1	XM_011530907.3	c.-17+229G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000374029.2	c.-16-697G>A		intron_variant		5		P1
GJB1	ENST00000447581.2	c.-17+229G>A		intron_variant		5		P1
GJB1	ENST00000645009.2	c.-16-697G>A		intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.661 AC: 72306 AN: 109426 Hom.: 17647 Cov.: 22 AF XY: 0.650 AC XY: 20625 AN XY: 31714

Gnomad AFR AF: 0.813

Gnomad AMI AF: 0.601

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.518

Gnomad EAS AF: 0.757

Gnomad SAS AF: 0.569

Gnomad FIN AF: 0.621

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.584

Gnomad OTH AF: 0.651

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.661 AC: 72363 AN: 109473 Hom.: 17658 Cov.: 22 AF XY: 0.651 AC XY: 20673 AN XY: 31771

Gnomad4 AFR AF: 0.813

Gnomad4 AMR AF: 0.662

Gnomad4 ASJ AF: 0.518

Gnomad4 EAS AF: 0.757

Gnomad4 SAS AF: 0.568

Gnomad4 FIN AF: 0.621

Gnomad4 NFE AF: 0.584

Gnomad4 OTH AF: 0.657

Alfa AF: 0.570 Hom.: 15244

Bravo AF: 0.674

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Charcot-Marie-Tooth Neuropathy X Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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	-0.88
Cadd	Benign	0.0020
Dann	Benign	0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs6525485; hg19: chrX-70442845;