rs7333214

chr13-20222358-C-Achr13-20222358-C-Gchr13-20222358-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001110219.3(GJB6):c.*337G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 229,700 control chromosomes in the GnomAD database, including 7,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (6113 hom., cov: 32)
  • Exomes 𝑓: 0.15 (1218 hom.)
• Consequence: GJB6 NM_001110219.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.715

Genes affected

GJB6 (HGNC:4288): (gap junction protein beta 6) Gap junctions allow the transport of ions and metabolites between the cytoplasm of adjacent cells. They are formed by two hemichannels, made up of six connexin proteins assembled in groups. Each connexin protein has four transmembrane segments, two extracellular loops, a cytoplasmic loop formed between the two inner transmembrane segments, and the N- and C-terminus both being in the cytoplasm. The specificity of the gap junction is determined by which connexin proteins comprise the hemichannel. In the past, connexin protein names were based on their molecular weight, however the new nomenclature uses sequential numbers based on which form (alpha or beta) of the gap junction is present. This gene encodes one of the connexin proteins. Mutations in this gene have been found in some forms of deafness and in some families with hidrotic ectodermal dysplasia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 13-20222358-C-A is Benign according to our data. Variant chr13-20222358-C-A is described in ClinVar as [Benign]. Clinvar id is 311376.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB6	NM_001110219.3	c.*337G>T		3_prime_UTR_variant	5/5	ENST00000647029.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB6	ENST00000647029.1	c.*337G>T		3_prime_UTR_variant	5/5		NM_001110219.3	P1

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37101 AN: 151990 Hom.: 6087 Cov.: 32

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.229

GnomAD4 exome AF: 0.155 AC: 12004 AN: 77590 Hom.: 1218 Cov.: 0 AF XY: 0.151 AC XY: 6065 AN XY: 40286

Gnomad4 AFR exome AF: 0.441

Gnomad4 AMR exome AF: 0.124

Gnomad4 ASJ exome AF: 0.249

Gnomad4 EAS exome AF: 0.281

Gnomad4 SAS exome AF: 0.0886

Gnomad4 FIN exome AF: 0.0903

Gnomad4 NFE exome AF: 0.138

Gnomad4 OTH exome AF: 0.181

GnomAD4 genome AF: 0.244 AC: 37178 AN: 152110 Hom.: 6113 Cov.: 32 AF XY: 0.240 AC XY: 17836 AN XY: 74360

Gnomad4 AFR AF: 0.472

Gnomad4 AMR AF: 0.164

Gnomad4 ASJ AF: 0.261

Gnomad4 EAS AF: 0.261

Gnomad4 SAS AF: 0.115

Gnomad4 FIN AF: 0.104

Gnomad4 NFE AF: 0.155

Gnomad4 OTH AF: 0.226

Alfa AF: 0.169 Hom.: 4337

Bravo AF: 0.263

Asia WGS AF: 0.172 AC: 599 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hidrotic ectodermal dysplasia syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	9.3
Dann	Benign	0.55

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: rs7333214; hg19: chr13-20796497;