X-71216669-C-T

Variant names:

• chrX-71216669-C-T
• rs11094200
• ENST00000675368.1:c.-608C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000675368.1(GJB1):​c.-608C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 109,893 control chromosomes in the GnomAD database, including 1,456 homozygotes. There are 5,409 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (1456 hom., 5409 hem., cov: 21)
• Consequence: GJB1 ENST00000675368.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.475
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_001097642.3	c.-17+1379C>T		intron_variant	Intron 1 of 1		NP_001091111.1
GJB1	NM_001440770.1	c.-200+1379C>T		intron_variant	Intron 1 of 2		NP_001427699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000675368.1	c.-608C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 2			ENSP00000501757.1
GJB1	ENST00000675368.1	c.-608C>T		5_prime_UTR_variant	Exon 1 of 2			ENSP00000501757.1
GJB1	ENST00000374029.2	c.-17+1398C>T		intron_variant	Intron 1 of 1	5		ENSP00000363141.1

Frequencies

GnomAD3 genomes AF: 0.179 AC: 19690 AN: 109841 Hom.: 1451 Cov.: 21

Gnomad AFR AF: 0.261

Gnomad AMI AF: 0.0486

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.211

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.159

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

GnomAD4 genome AF: 0.179 AC: 19704 AN: 109893 Hom.: 1456 Cov.: 21 AF XY: 0.168 AC XY: 5409 AN XY: 32205

African (AFR) AF: 0.261 AC: 7851 AN: 30104

American (AMR) AF: 0.130 AC: 1333 AN: 10235

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 333 AN: 2634

East Asian (EAS) AF: 0.131 AC: 455 AN: 3482

South Asian (SAS) AF: 0.101 AC: 262 AN: 2584

European-Finnish (FIN) AF: 0.157 AC: 909 AN: 5790

Middle Eastern (MID) AF: 0.212 AC: 46 AN: 217

European-Non Finnish (NFE) AF: 0.157 AC: 8244 AN: 52671

Other (OTH) AF: 0.159 AC: 238 AN: 1497

Alfa AF: 0.182 Hom.: 5621

Bravo AF: 0.182

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.5
DANN	Benign	0.68
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism (auto)

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: rs11094200; hg19: chrX-70436519;