NM_024009.3:c.652_663delCTGCACAAGGAC

Variant names:

• chr1-34785412-GCCTGCACAAGGA-G
• rs727503069
• NM_024009.3:c.652_663delCTGCACAAGGAC

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM4 BS1 BS2

The NM_024009.3(GJB3):​c.652_663delCTGCACAAGGAC​(p.Leu218_Asp221del) variant causes a conservative 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 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.89

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]

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

ENSG00000255811 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• 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 rank	MANE	Protein	UniProt
GJB3	NM_024009.3	c.652_663delCTGCACAAGGAC	p.Leu218_Asp221del	conservative_inframe_deletion	Exon 2 of 2	ENST00000373366.3	NP_076872.1
GJB3	NM_001005752.2	c.652_663delCTGCACAAGGAC	p.Leu218_Asp221del	conservative_inframe_deletion	Exon 2 of 2		NP_001005752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB3	ENST00000373366.3	c.652_663delCTGCACAAGGAC	p.Leu218_Asp221del	conservative_inframe_deletion	Exon 2 of 2	1	NM_024009.3	ENSP00000362464.2
GJB3	ENST00000373362.3	c.652_663delCTGCACAAGGAC	p.Leu218_Asp221del	conservative_inframe_deletion	Exon 2 of 2	1		ENSP00000362460.3
SMIM12	ENST00000426886.1	n.208-67015_208-67004delTCCTTGTGCAGG		intron_variant	Intron 2 of 4	1		ENSP00000429902.1
ENSG00000255811	ENST00000542839.1	n.110+2564_110+2575delTCCTTGTGCAGG		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152162 Hom.: 0 Cov.: 32

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: 70 AN: 251276 Hom.: 1 AF XY: 0.000250 AC XY: 34 AN XY: 135832

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.: 1 AF XY: 0.000237 AC XY: 172 AN XY: 727232

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: 33 AN: 152162 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74332

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.: 1

Bravo AF: 0.000230

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Dec 29, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 14, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jan 22, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, ∆LHKD218-221. 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

Feb 27, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727503069; hg19: chr1-35251013;