rs768372993

Positions:

chr1-34785412-GCCTGCACAAGGA-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PM1PM4BS1BS2

The NM_024009.3(GJB3):c.652_663del(p.Leu218_Asp221del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 1,614,024 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 1 hom. )

Consequence

GJB3
NM_024009.3 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 1.89

Variant links:

Genes affected

GJB3 (HGNC:4285): (gap junction protein beta 3) This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. Mutations in this gene can cause non-syndromic deafness or erythrokeratodermia variabilis, a skin disorder. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

GJB3 links:

SMIM12 (HGNC:25154): (small integral membrane protein 12) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SMIM12 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a chain Gap junction beta-3 protein (size 269) in uniprot entity CXB3_HUMAN there are 17 pathogenic changes around while only 4 benign (81%) in NM_024009.3

PM4

Nonframeshift variant in NON repetitive region in NM_024009.3.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000236 (345/1461862) while in subpopulation MID AF= 0.00486 (28/5764). AF 95% confidence interval is 0.00345. There are 1 homozygotes in gnomad4_exome. There are 172 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd4 at 33 AD,Digenic gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB3	NM_024009.3 linkuse as main transcript	c.652_663del	p.Leu218_Asp221del	inframe_deletion	2/2	ENST00000373366.3	NP_076872.1
GJB3	NM_001005752.2 linkuse as main transcript	c.652_663del	p.Leu218_Asp221del	inframe_deletion	2/2		NP_001005752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
GJB3	ENST00000373366.3 linkuse as main transcript	c.652_663del	p.Leu218_Asp221del	inframe_deletion	2/2	1	NM_024009.3	ENSP00000362464	P1
GJB3	ENST00000373362.3 linkuse as main transcript	c.652_663del	p.Leu218_Asp221del	inframe_deletion	2/2	1		ENSP00000362460	P1
SMIM12	ENST00000426886.1 linkuse as main transcript	c.208-67015_208-67004del		intron_variant, NMD_transcript_variant		1		ENSP00000429902
	ENST00000542839.1 linkuse as main transcript	n.110+2564_110+2575del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000279

AC:

AN:

251276

Hom.:

AF XY:

0.000250

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.000236

AC:

345

AN:

1461862

Hom.:

AF XY:

0.000237

AC XY:

172

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00157

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000179

Gnomad4 OTH exome

AF:

0.000662

GnomAD4 genome

AF:

0.000217

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000521

Hom.:

Bravo

AF:

0.000230

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 29, 2017	The GJB3 p.Leu218_Asp221del variant (rs727503069) has not been reported in association with hearing loss or deafness, but it has been identified in a family with erythrokeratodermia variabilis without hearing loss; however, this variant was identified in both affected and unaffected individuals whereas another variant that was on the same allele (in cis) and arose de novo in one individual was found only in affected family members (Richard 2000). Collectively, these observations suggest that the p.Leu218_Asp221del is not responsible for disease. Furthermore, the four amino acids that are removed by this in-frame deletion are poorly conserved (UCSC). The p.Leu218_Asp221del variant is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.14% in the Ashkenazi Jewish population (identified in 14 out of 10,148 chromosomes), and is found in the ClinVar database (Variant ID: 163536). Based on the available evidence, the p.Leu218_Asp221del variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 22, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	Observed in both affected and unaffected individuals in a family with erythrokeratodermia variabilis in published literature; affected patients also harbored a de novo variant on the same allele (in cis) (Richard et al., 2000); In-frame deletion of 4 amino acids in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 10798362) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2023	This variant, c.652_663del, results in the deletion of 4 amino acid(s) of the GJB3 protein (p.Leu218_Asp221del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs768372993, gnomAD 0.1%). This variant has been observed in individual(s) with clinical features of autosomal dominant erythrokeratodermia variabilis (PMID: 10798362). This variant is also known as 652del12, ‚àÜLHKD218-221. ClinVar contains an entry for this variant (Variation ID: 163536). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 27, 2015

p.Leu218_Asp221del in exon 2 of GJB3: This variant is not expected to have clini cal significance because the region affected by this 4 amino acid in-frame delet ion is poorly conserved across mammals and evolutionarily distant species. In ad dition, in a family with erythrokeratodermia variabalis (EKV) without hearing lo ss, this variant was detected in both affected and unaffected family members, wh ile a variant that arose de novo on the same allele (in cis) in one individual s egregated with disease in her children, indicating that the de novo variant is c ausative for the EKV, and the p.Leu218_Asp221del is unrelated to the disease (Ri chard 2000). This variant has also been identified in 2/8250 European American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/E VS/). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over