rs35002004

Positions:

• chr13-20222992-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001110219.3(GJB6):​c.489G>A​(p.Leu163Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,614,148 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0030 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (14 hom.)
• Consequence: GJB6 NM_001110219.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.18

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 13-20222992-C-T is Benign according to our data. Variant chr13-20222992-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45503.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=2}. Variant chr13-20222992-C-T is described in Lovd as [Likely_benign]. Variant chr13-20222992-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00303 (461/152284) while in subpopulation AMR AF= 0.00595 (91/15290). AF 95% confidence interval is 0.00496. There are 5 homozygotes in gnomad4. There are 218 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB6	NM_001110219.3	c.489G>A	p.Leu163Leu	synonymous_variant	5/5	ENST00000647029.1	NP_001103689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB6	ENST00000647029.1	c.489G>A	p.Leu163Leu	synonymous_variant	5/5		NM_001110219.3	ENSP00000493834.1

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 460 AN: 152166 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00397

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00324 AC: 814 AN: 251480 Hom.: 8 AF XY: 0.00318 AC XY: 432 AN XY: 135912

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.0121

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00420

Gnomad OTH exome AF: 0.00521

GnomAD4 exome AF: 0.00333 AC: 4867 AN: 1461864 Hom.: 14 Cov.: 32 AF XY: 0.00324 AC XY: 2355 AN XY: 727236

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00349

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00128

Gnomad4 FIN exome AF: 0.00165

Gnomad4 NFE exome AF: 0.00354

Gnomad4 OTH exome AF: 0.00389

GnomAD4 genome AF: 0.00303 AC: 461 AN: 152284 Hom.: 5 Cov.: 32 AF XY: 0.00293 AC XY: 218 AN XY: 74466

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00595

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.000847

Gnomad4 NFE AF: 0.00397

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00413 Hom.: 1

Bravo AF: 0.00310

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00474

EpiControl AF: 0.00480

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	GJB6: BP4, BP7, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 18, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2021	This variant is associated with the following publications: (PMID: 10610709) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 17, 2013

This variant is not expected to have clinical significance because it does not a lter an amino acid residue, is not located within the splice consensus sequence and has been identified in 0.5% (43/8600) of European American chromosomes by th e NHLBI Exome sequencing project (http://evs.gs.washington.edu/EVS/; dbSNP rs350 02004). -

Hidrotic ectodermal dysplasia syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hidrotic ectodermal dysplasia syndrome;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B;C2675237:Autosomal dominant nonsyndromic hearing loss 3B Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.4
DANN	Benign	0.70

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: rs35002004; hg19: chr13-20797131;