rs9315400

Variant names:

• chr13-20225900-C-T
• rs9315400
• NM_001110219.3:c.-15-2405G>A

Variant summary

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

The NM_001110219.3(GJB6):​c.-15-2405G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 152,002 control chromosomes in the GnomAD database, including 11,703 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 0.38 (11703 hom., cov: 31)
• Consequence: GJB6 NM_001110219.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.211
• Publications: 4 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB6	NM_001110219.3	c.-15-2405G>A		intron_variant	Intron 4 of 4	ENST00000647029.1	NP_001103689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB6	ENST00000647029.1	c.-15-2405G>A		intron_variant	Intron 4 of 4		NM_001110219.3	ENSP00000493834.1

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58227 AN: 151884 Hom.: 11689 Cov.: 31

Gnomad AFR AF: 0.319

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.376

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

GnomAD4 genome AF: 0.383 AC: 58277 AN: 152002 Hom.: 11703 Cov.: 31 AF XY: 0.386 AC XY: 28655 AN XY: 74304

African (AFR) AF: 0.319 AC: 13242 AN: 41458

American (AMR) AF: 0.536 AC: 8188 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1116 AN: 3466

East Asian (EAS) AF: 0.400 AC: 2062 AN: 5160

South Asian (SAS) AF: 0.491 AC: 2359 AN: 4806

European-Finnish (FIN) AF: 0.370 AC: 3915 AN: 10582

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.385 AC: 26175 AN: 67944

Other (OTH) AF: 0.378 AC: 800 AN: 2116

Alfa AF: 0.389 Hom.: 3734

Bravo AF: 0.393

Asia WGS AF: 0.492 AC: 1710 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.61
DANN	Benign	0.80
PhyloP100		-0.21
PromoterAI		-0.0036	Neutral
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: rs9315400; hg19: chr13-20800039;