X-71223079-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001097642.3(GJB1):c.-16-613C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00645 in 118,842 control chromosomes in the GnomAD database, including 7 homozygotes. There are 208 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 0.0068 (7 hom., 206 hem., cov: 22)
  • Exomes 𝑓: 0.00086 (0 hom. 2 hem.)
• Consequence: GJB1 NM_001097642.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.08

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant X-71223079-C-T is Benign according to our data. Variant chrX-71223079-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1203086.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0068 (761/111899) while in subpopulation AFR AF= 0.023 (709/30800). AF 95% confidence interval is 0.0216. There are 7 homozygotes in gnomad4. There are 206 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_001097642.3	c.-16-613C>T		intron_variant
GJB1	XM_011530907.3	c.-17+313C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB1	ENST00000374029.2	c.-16-613C>T		intron_variant		5		P1
GJB1	ENST00000447581.2	c.-17+313C>T		intron_variant		5		P1
GJB1	ENST00000645009.2	c.-16-613C>T		intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.00680 AC: 761 AN: 111846 Hom.: 7 Cov.: 22 AF XY: 0.00605 AC XY: 206 AN XY: 34036

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.000378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000162

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000170

Gnomad OTH AF: 0.00724

GnomAD4 exome AF: 0.000864 AC: 6 AN: 6943 Hom.: 0 AF XY: 0.00136 AC XY: 2 AN XY: 1471

Gnomad4 AFR exome AF: 0.0301

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00292

GnomAD4 genome AF: 0.00680 AC: 761 AN: 111899 Hom.: 7 Cov.: 22 AF XY: 0.00604 AC XY: 206 AN XY: 34099

Gnomad4 AFR AF: 0.0230

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.000378

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000162

Gnomad4 NFE AF: 0.000170

Gnomad4 OTH AF: 0.00715

Alfa AF: 0.00744 Hom.: 19

Bravo AF: 0.00805

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

Oct 21, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
Cadd	Benign	19
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: rs185380563; hg19: chrX-70442929;