rs587777112

Variant names:

• chr3-184357431-G-GC
• rs587777112
• NM_004366.6:c.828dupG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004366.6(CLCN2):​c.828dupG​(p.Arg277AlafsTer23) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLCN2 NM_004366.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.86
• Publications: 2 publications found

Genes affected

CLCN2 (HGNC:2020): (chloride voltage-gated channel 2) This gene encodes a voltage-gated chloride channel. The encoded protein is a transmembrane protein that maintains chloride ion homeostasis in various cells. Defects in this gene may be a cause of certain epilepsies. Four transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

CLCN2 Gene-Disease associations (from GenCC):

• leukoencephalopathy with mild cerebellar ataxia and white matter edema

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• epilepsy, idiopathic generalized, susceptibility to, 11

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• familial hyperaldosteronism type II

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• epilepsy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-184357431-G-GC is Pathogenic according to our data. Variant chr3-184357431-G-GC is described in ClinVar as Pathogenic. ClinVar VariationId is 100632.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004366.6. 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
	CLCN2	NM_004366.6	MANE Select	c.828dupG	p.Arg277AlafsTer23	frameshift	Exon 8 of 24	NP_004357.3
	CLCN2	NM_001171087.3		c.828dupG	p.Arg277AlafsTer23	frameshift	Exon 8 of 24	NP_001164558.1
	CLCN2	NM_001171089.3		c.828dupG	p.Arg277AlafsTer23	frameshift	Exon 8 of 23	NP_001164560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN2	ENST00000265593.9	TSL:1 MANE Select	c.828dupG	p.Arg277AlafsTer23	frameshift	Exon 8 of 24	ENSP00000265593.4
	CLCN2	ENST00000344937.11	TSL:1	c.828dupG	p.Arg277AlafsTer23	frameshift	Exon 8 of 24	ENSP00000345056.7
	CLCN2	ENST00000457512.1	TSL:2	c.828dupG	p.Arg277AlafsTer23	frameshift	Exon 8 of 23	ENSP00000391928.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leukoencephalopathy with mild cerebellar ataxia and white matter edema Pathogenic:1 Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Jul 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:1

Sep 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg277Alafs*23) in the CLCN2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLCN2 are known to be pathogenic (PMID: 23707145). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with CLCN2-related conditions (PMID: 23707145). ClinVar contains an entry for this variant (Variation ID: 100632). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs587777112; hg19: chr3-184075219;