rs144164281

Positions:

• chr3-184352474-C-G
• chr3-184352474-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000265593.9(CLCN2):​c.2240G>C​(p.Arg747Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R747H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLCN2 ENST00000265593.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.86

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3116825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN2	NM_004366.6	c.2240G>C	p.Arg747Pro	missense_variant	20/24	ENST00000265593.9	NP_004357.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN2	ENST00000265593.9	c.2240G>C	p.Arg747Pro	missense_variant	20/24	1	NM_004366.6	ENSP00000265593	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T;.;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.11
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Uncertain	-0.074	T
MutationAssessor	Benign	1.4	L;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.65	N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.26	T;T;T;T
Sift4G	Benign	0.29	T;T;T;T
Polyphen		0.0030	B;B;.;.
Vest4		0.51
MutPred		0.29		Loss of MoRF binding (P = 0.002);.;.;Loss of MoRF binding (P = 0.002);
MVP		0.91
MPC		0.42
ClinPred		0.72	D
GERP RS		4.5
Varity_R		0.20
gMVP		0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs144164281; hg19: chr3-184070262;