X-71223451-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000166.6(GJB1):c.-17+116C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0204 in 436,540 control chromosomes in the GnomAD database, including 95 homozygotes. There are 2,722 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.024 (41 hom., 648 hem., cov: 23)
  • Exomes 𝑓: 0.019 (54 hom. 2074 hem.)
• Consequence: GJB1 NM_000166.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.119

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-71223451-C-T is Benign according to our data. Variant chrX-71223451-C-T is described in ClinVar as [Benign]. Clinvar id is 380814.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-71223451-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0238 (2623/110429) while in subpopulation AFR AF= 0.0374 (1136/30341). AF 95% confidence interval is 0.0356. There are 41 homozygotes in gnomad4. There are 648 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 41 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.-17+116C>T		intron_variant		ENST00000361726.7
GJB1	NM_001097642.3	c.-16-241C>T		intron_variant
GJB1	XM_011530907.3	c.-16-241C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.-17+116C>T		intron_variant		1	NM_000166.6	P1

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 2625 AN: 110380 Hom.: 41 Cov.: 23 AF XY: 0.0198 AC XY: 648 AN XY: 32686

Gnomad AFR AF: 0.0375

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0149

Gnomad ASJ AF: 0.0566

Gnomad EAS AF: 0.000566

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.00659

Gnomad MID AF: 0.0565

Gnomad NFE AF: 0.0204

Gnomad OTH AF: 0.0258

GnomAD4 exome AF: 0.0193 AC: 6303 AN: 326111 Hom.: 54 AF XY: 0.0188 AC XY: 2074 AN XY: 110139

Gnomad4 AFR exome AF: 0.0458

Gnomad4 AMR exome AF: 0.0123

Gnomad4 ASJ exome AF: 0.0553

Gnomad4 EAS exome AF: 0.0000440

Gnomad4 SAS exome AF: 0.00739

Gnomad4 FIN exome AF: 0.0108

Gnomad4 NFE exome AF: 0.0207

Gnomad4 OTH exome AF: 0.0259

GnomAD4 genome AF: 0.0238 AC: 2623 AN: 110429 Hom.: 41 Cov.: 23 AF XY: 0.0198 AC XY: 648 AN XY: 32747

Gnomad4 AFR AF: 0.0374

Gnomad4 AMR AF: 0.0149

Gnomad4 ASJ AF: 0.0566

Gnomad4 EAS AF: 0.000568

Gnomad4 SAS AF: 0.00726

Gnomad4 FIN AF: 0.00659

Gnomad4 NFE AF: 0.0204

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0126 Hom.: 88

Bravo AF: 0.0263

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 01, 2016

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	1.1
Dann	Benign	0.78

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: rs111853447; hg19: chrX-70443301;