rs587777110

Variant names:

• chr3-184358227-TGATGAG-T
• rs587777110
• NM_004366.6:c.430_435delCTCATC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM4 PP3 PP5

The NM_004366.6(CLCN2):​c.430_435delCTCATC​(p.Leu144_Ile145del) variant causes a conservative inframe deletion 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 (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CLCN2 NM_004366.6 conservative_inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.31
• Publications: 1 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004366.6.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 3-184358227-TGATGAG-T is Pathogenic according to our data. Variant chr3-184358227-TGATGAG-T is described in ClinVar as Pathogenic. ClinVar VariationId is 100630.Status of the report is no_assertion_criteria_provided, 0 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.430_435delCTCATC	p.Leu144_Ile145del	conservative_inframe_deletion	Exon 4 of 24	NP_004357.3
	CLCN2	NM_001171087.3		c.430_435delCTCATC	p.Leu144_Ile145del	conservative_inframe_deletion	Exon 4 of 24	NP_001164558.1
	CLCN2	NM_001171089.3		c.430_435delCTCATC	p.Leu144_Ile145del	conservative_inframe_deletion	Exon 4 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.430_435delCTCATC	p.Leu144_Ile145del	conservative_inframe_deletion	Exon 4 of 24	ENSP00000265593.4
	CLCN2	ENST00000344937.11	TSL:1	c.430_435delCTCATC	p.Leu144_Ile145del	conservative_inframe_deletion	Exon 4 of 24	ENSP00000345056.7
	CLCN2	ENST00000457512.1	TSL:2	c.430_435delCTCATC	p.Leu144_Ile145del	conservative_inframe_deletion	Exon 4 of 23	ENSP00000391928.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Jul 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587777110; hg19: chr3-184076015;