rs863225247

Variant names:

• chr3-184359065-C-G
• rs863225247
• NM_004366.6:c.130G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-184359065-C-G
• chr3-184359065-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004366.6(CLCN2):​c.130G>C​(p.Gly44Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLCN2 NM_004366.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.76
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26920915).

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.130G>C	p.Gly44Arg	missense	Exon 2 of 24	NP_004357.3
	CLCN2	NM_001171087.3		c.130G>C	p.Gly44Arg	missense	Exon 2 of 24	NP_001164558.1
	CLCN2	NM_001171089.3		c.130G>C	p.Gly44Arg	missense	Exon 2 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.130G>C	p.Gly44Arg	missense	Exon 2 of 24	ENSP00000265593.4
	CLCN2	ENST00000344937.11	TSL:1	c.130G>C	p.Gly44Arg	missense	Exon 2 of 24	ENSP00000345056.7
	CLCN2	ENST00000457512.1	TSL:2	c.130G>C	p.Gly44Arg	missense	Exon 2 of 23	ENSP00000391928.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461368 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726990

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52902

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.96	N
REVEL	Uncertain	0.55
Sift	Benign	0.51	T
Sift4G	Benign	0.54	T
Polyphen		0.50	P
Vest4		0.79
MutPred		0.26		Gain of MoRF binding (P = 0.0106)
MVP		0.81
MPC		0.45
ClinPred		0.24	T
GERP RS		4.5
PromoterAI		-0.044	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.37
Mutation Taster		=22/78	disease causing

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: rs863225247; hg19: chr3-184076853;