13-20222992-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.18

Publications

4 publications found

Variant links:

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]

GJB6 Gene-Disease associations (from GenCC):

Clouston syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
KID syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
autosomal dominant nonsyndromic hearing loss 3B
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
autosomal recessive nonsyndromic hearing loss 1B
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
nonsyndromic genetic hearing loss
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

GJB6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 45503.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB6	NM_001110219.3 link	c.489G>A	p.Leu163Leu	synonymous_variant	Exon 5 of 5	ENST00000647029.1	NP_001103689.1	O95452A0A024RDS4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB6	ENST00000647029.1 link	c.489G>A	p.Leu163Leu	synonymous_variant	Exon 5 of 5		NM_001110219.3	ENSP00000493834.1		O95452

Frequencies

GnomAD3 genomes

AF:

0.00302

AC:

460

AN:

152166

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00324

AC:

814

AN:

251480

AF XY:

0.00318

show subpopulations

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 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.:

Cov.:

AF XY:

0.00324

AC XY:

2355

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.000657

AC:

AN:

33478

American (AMR)

AF:

0.00349

AC:

156

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

293

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00128

AC:

110

AN:

86258

European-Finnish (FIN)

AF:

0.00165

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00416

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00354

AC:

3939

AN:

1111988

Other (OTH)

AF:

0.00389

AC:

235

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

305

609

914

1218

1523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

280

420

560

700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00303

AC:

461

AN:

152284

Hom.:

Cov.:

AF XY:

0.00293

AC XY:

218

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000650

AC:

AN:

41554

American (AMR)

AF:

0.00595

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0118

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00249

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000847

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00397

AC:

270

AN:

68030

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00384

Hom.:

Bravo

AF:

0.00310

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00474

EpiControl

AF:

0.00480

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jul 16, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 10610709) -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GJB6: BP4, BP7, BS2 -

Feb 18, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hidrotic ectodermal dysplasia syndrome

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not specified

Benign:1

Oct 17, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B;C2675237:Autosomal dominant nonsyndromic hearing loss 3B

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

8.4

(source)

DANN

Benign

0.70

PhyloP100

2.2

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over