13-20224101-A-G

Variant names:

• chr13-20224101-A-G
• rs877098
• NM_001110219.3:c.-15-606T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001110219.3(GJB6):​c.-15-606T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.565 in 151,966 control chromosomes in the GnomAD database, including 24,470 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (24470 hom., cov: 32)
• Consequence: GJB6 NM_001110219.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.463
• Publications: 10 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: 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.659 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB6	NM_001110219.3	MANE Select	c.-15-606T>C		intron	N/A	NP_001103689.1
	GJB6	NM_001110220.3		c.-15-606T>C		intron	N/A	NP_001103690.1
	GJB6	NM_001110221.3		c.-15-606T>C		intron	N/A	NP_001103691.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB6	ENST00000647029.1	MANE Select	c.-15-606T>C		intron	N/A	ENSP00000493834.1
	GJB6	ENST00000241124.11	TSL:1	c.-15-606T>C		intron	N/A	ENSP00000241124.6
	GJB6	ENST00000400065.7	TSL:1	c.-15-606T>C		intron	N/A	ENSP00000382938.3

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85718 AN: 151848 Hom.: 24442 Cov.: 32

Gnomad AFR AF: 0.573

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.616

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.556

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.565 AC: 85806 AN: 151966 Hom.: 24470 Cov.: 32 AF XY: 0.564 AC XY: 41910 AN XY: 74260

African (AFR) AF: 0.573 AC: 23745 AN: 41442

American (AMR) AF: 0.670 AC: 10225 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 2017 AN: 3466

East Asian (EAS) AF: 0.663 AC: 3408 AN: 5140

South Asian (SAS) AF: 0.616 AC: 2962 AN: 4812

European-Finnish (FIN) AF: 0.474 AC: 5012 AN: 10570

Middle Eastern (MID) AF: 0.479 AC: 140 AN: 292

European-Non Finnish (NFE) AF: 0.539 AC: 36645 AN: 67956

Other (OTH) AF: 0.556 AC: 1175 AN: 2114

Alfa AF: 0.553 Hom.: 25633

Bravo AF: 0.583

Asia WGS AF: 0.650 AC: 2257 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.6
DANN	Benign	0.50
PhyloP100		0.46
Mutation Taster		=100/0	polymorphism (auto)

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: rs877098; hg19: chr13-20798240;