chr13-20223466-C-T

Variant names:

• chr13-20223466-C-T
• rs150075979
• NM_001110219.3:c.15G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001110219.3(GJB6):​c.15G>A​(p.Thr5Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 1,613,976 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T5T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: GJB6 NM_001110219.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -2.05
• Publications: 2 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 13-20223466-C-T is Benign according to our data. Variant chr13-20223466-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45501.
• BP7: Synonymous conserved (PhyloP=-2.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00102 (155/152254) while in subpopulation AFR AF = 0.00344 (143/41522). AF 95% confidence interval is 0.00298. There are 2 homozygotes in GnomAd4. There are 69 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.15G>A	p.Thr5Thr	synonymous	Exon 5 of 5	NP_001103689.1	O95452
	GJB6	NM_001110220.3		c.15G>A	p.Thr5Thr	synonymous	Exon 4 of 4	NP_001103690.1	O95452
	GJB6	NM_001110221.3		c.15G>A	p.Thr5Thr	synonymous	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.15G>A	p.Thr5Thr	synonymous	Exon 5 of 5	ENSP00000493834.1	O95452
	GJB6	ENST00000241124.11	TSL:1	c.15G>A	p.Thr5Thr	synonymous	Exon 3 of 3	ENSP00000241124.6	O95452
	GJB6	ENST00000400065.7	TSL:1	c.15G>A	p.Thr5Thr	synonymous	Exon 3 of 3	ENSP00000382938.3	O95452

Frequencies

GnomAD3 genomes AF: 0.000993 AC: 151 AN: 152136 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00336

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000344 AC: 86 AN: 249942 AF XY: 0.000273

Gnomad AFR exome AF: 0.00439

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000140 AC: 205 AN: 1461722 Hom.: 0 Cov.: 32 AF XY: 0.000129 AC XY: 94 AN XY: 727168

African (AFR) AF: 0.00403 AC: 135 AN: 33476

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111874

Other (OTH) AF: 0.000447 AC: 27 AN: 60390

GnomAD4 genome AF: 0.00102 AC: 155 AN: 152254 Hom.: 2 Cov.: 32 AF XY: 0.000927 AC XY: 69 AN XY: 74462

African (AFR) AF: 0.00344 AC: 143 AN: 41522

American (AMR) AF: 0.000588 AC: 9 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000733 Hom.: 0

Bravo AF: 0.00117

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.6
DANN	Benign	0.47
PhyloP100		-2.1
Mutation Taster		=99/1	polymorphism

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: rs150075979; hg19: chr13-20797605; COSMIC: COSV53831831;