rs7333214

Variant names:

• chr13-20222358-C-A
• rs7333214
• NM_001110219.3:c.*337G>T

Your query was ambiguous. Multiple possible variants found:

• chr13-20222358-C-A
• chr13-20222358-C-G
• chr13-20222358-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001110219.3(GJB6):​c.*337G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 229,700 control chromosomes in the GnomAD database, including 7,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (6113 hom., cov: 32)
  • Exomes 𝑓: 0.15 (1218 hom.)
• Consequence: GJB6 NM_001110219.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.715
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 13-20222358-C-A is Benign according to our data. Variant chr13-20222358-C-A is described in ClinVar as Benign. ClinVar VariationId is 311376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB6	NM_001110219.3	c.*337G>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000647029.1	NP_001103689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB6	ENST00000647029.1	c.*337G>T		3_prime_UTR_variant	Exon 5 of 5		NM_001110219.3	ENSP00000493834.1

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37101 AN: 151990 Hom.: 6087 Cov.: 32

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.156

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.229

GnomAD4 exome AF: 0.155 AC: 12004 AN: 77590 Hom.: 1218 Cov.: 0 AF XY: 0.151 AC XY: 6065 AN XY: 40286

African (AFR) AF: 0.441 AC: 979 AN: 2220

American (AMR) AF: 0.124 AC: 550 AN: 4420

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 613 AN: 2460

East Asian (EAS) AF: 0.281 AC: 1346 AN: 4794

South Asian (SAS) AF: 0.0886 AC: 524 AN: 5914

European-Finnish (FIN) AF: 0.0903 AC: 360 AN: 3986

Middle Eastern (MID) AF: 0.188 AC: 58 AN: 308

European-Non Finnish (NFE) AF: 0.138 AC: 6728 AN: 48818

Other (OTH) AF: 0.181 AC: 846 AN: 4670

GnomAD4 genome AF: 0.244 AC: 37178 AN: 152110 Hom.: 6113 Cov.: 32 AF XY: 0.240 AC XY: 17836 AN XY: 74360

African (AFR) AF: 0.472 AC: 19562 AN: 41454

American (AMR) AF: 0.164 AC: 2503 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 907 AN: 3470

East Asian (EAS) AF: 0.261 AC: 1353 AN: 5176

South Asian (SAS) AF: 0.115 AC: 553 AN: 4824

European-Finnish (FIN) AF: 0.104 AC: 1099 AN: 10586

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10524 AN: 68006

Other (OTH) AF: 0.226 AC: 477 AN: 2114

Alfa AF: 0.188 Hom.: 9505

Bravo AF: 0.263

Asia WGS AF: 0.172 AC: 599 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hidrotic ectodermal dysplasia syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.3
DANN	Benign	0.55
PhyloP100		0.71
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: rs7333214; hg19: chr13-20796497;