rs111033338

Variant names:

• chr13-20222886-A-T
• rs111033338
• NM_001110219.3:c.595T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001110219.3(GJB6):​c.595T>A​(p.Ser199Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00685 in 1,614,150 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (49 hom.)
• Consequence: GJB6 NM_001110219.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 6.10
• Publications: 13 publications found

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: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, ClinGen, Ambry Genetics, G2P
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021862358).
• BP6: Variant 13-20222886-A-T is Benign according to our data. Variant chr13-20222886-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00425 (648/152300) while in subpopulation NFE AF = 0.00739 (503/68034). AF 95% confidence interval is 0.00686. There are 5 homozygotes in GnomAd4. There are 303 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110219.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB6	NM_001110219.3	MANE Select	c.595T>A	p.Ser199Thr	missense	Exon 5 of 5	NP_001103689.1	O95452
	GJB6	NM_001110220.3		c.595T>A	p.Ser199Thr	missense	Exon 4 of 4	NP_001103690.1	O95452
	GJB6	NM_001110221.3		c.595T>A	p.Ser199Thr	missense	Exon 3 of 3	NP_001103691.1	O95452

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB6	ENST00000647029.1	MANE Select	c.595T>A	p.Ser199Thr	missense	Exon 5 of 5	ENSP00000493834.1	O95452
	GJB6	ENST00000241124.11	TSL:1	c.595T>A	p.Ser199Thr	missense	Exon 3 of 3	ENSP00000241124.6	O95452
	GJB6	ENST00000400065.7	TSL:1	c.595T>A	p.Ser199Thr	missense	Exon 3 of 3	ENSP00000382938.3	O95452

Frequencies

GnomAD3 genomes AF: 0.00426 AC: 648 AN: 152182 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00527

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00739

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00457 AC: 1150 AN: 251382 AF XY: 0.00447

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00568

Gnomad NFE exome AF: 0.00810

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00712 AC: 10404 AN: 1461850 Hom.: 49 Cov.: 32 AF XY: 0.00681 AC XY: 4956 AN XY: 727228

African (AFR) AF: 0.00111 AC: 37 AN: 33480

American (AMR) AF: 0.00141 AC: 63 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 53 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00616 AC: 329 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00866 AC: 9635 AN: 1111976

Other (OTH) AF: 0.00472 AC: 285 AN: 60392

GnomAD4 genome AF: 0.00425 AC: 648 AN: 152300 Hom.: 5 Cov.: 32 AF XY: 0.00407 AC XY: 303 AN XY: 74480

African (AFR) AF: 0.00132 AC: 55 AN: 41548

American (AMR) AF: 0.00163 AC: 25 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00527 AC: 56 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00739 AC: 503 AN: 68034

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00643 Hom.: 5

Bravo AF: 0.00397

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00640 AC: 55

ExAC AF: 0.00466 AC: 566

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00643

EpiControl AF: 0.00658

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	not specified (2)
-	-	1	Hidrotic ectodermal dysplasia syndrome (1)
-	-	1	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 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	0.00057	T
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.022	T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.039	D
Polyphen		1.0	D
Vest4		0.72
MVP		0.94
MPC		0.48
ClinPred		0.037	T
GERP RS		5.6
Varity_R		0.25
gMVP		0.94
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs111033338; hg19: chr13-20797025;