X-71223610-G-C

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.-16-82G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 898,661 control chromosomes in the GnomAD database, including 11 homozygotes. There are 320 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 0.0055 (7 hom., 180 hem., cov: 22)
  • Exomes 𝑓: 0.00072 (4 hom. 140 hem.)
• Consequence: GJB1 NM_000166.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.246

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=-0.91).
• BP6: Variant X-71223610-G-C is Benign according to our data. Variant chrX-71223610-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1203066.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00552 (613/111024) while in subpopulation AFR AF= 0.0184 (562/30521). AF 95% confidence interval is 0.0172. There are 7 homozygotes in gnomad4. There are 180 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB1	NM_000166.6	c.-16-82G>C		intron_variant		ENST00000361726.7
GJB1	NM_001097642.3	c.-16-82G>C		intron_variant
GJB1	XM_011530907.3	c.-16-82G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000361726.7	c.-16-82G>C		intron_variant		1	NM_000166.6	P1

Frequencies

GnomAD3 genomes AF: 0.00551 AC: 612 AN: 110975 Hom.: 7 Cov.: 22 AF XY: 0.00543 AC XY: 180 AN XY: 33171

Gnomad AFR AF: 0.0184

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00259

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000246

Gnomad OTH AF: 0.00537

GnomAD4 exome AF: 0.000717 AC: 565 AN: 787637 Hom.: 4 AF XY: 0.000625 AC XY: 140 AN XY: 224035

Gnomad4 AFR exome AF: 0.0177

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000199

Gnomad4 OTH exome AF: 0.00122

GnomAD4 genome AF: 0.00552 AC: 613 AN: 111024 Hom.: 7 Cov.: 22 AF XY: 0.00542 AC XY: 180 AN XY: 33230

Gnomad4 AFR AF: 0.0184

Gnomad4 AMR AF: 0.00259

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000246

Gnomad4 OTH AF: 0.00530

Bravo AF: 0.00605

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.61
Dann	Benign	0.34

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: rs192195270; hg19: chrX-70443460;