3-184353787-C-G

Variant names:

• chr3-184353787-C-G
• rs137852682
• NM_004366.6:c.1730G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004366.6(CLCN2):​c.1730G>C​(p.Arg577Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,453,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CLCN2 NM_004366.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.01

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN2	NM_004366.6	c.1730G>C	p.Arg577Pro	missense_variant	Exon 16 of 24	ENST00000265593.9	NP_004357.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN2	ENST00000265593.9	c.1730G>C	p.Arg577Pro	missense_variant	Exon 16 of 24	1	NM_004366.6	ENSP00000265593.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000428 AC: 1 AN: 233882 Hom.: 0 AF XY: 0.00000790 AC XY: 1 AN XY: 126626

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000950

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453824 Hom.: 0 Cov.: 33 AF XY: 0.00000277 AC XY: 2 AN XY: 722494

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;.;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	1.6	L;.;.;L
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Pathogenic	0.72
Sift	Benign	0.048	D;D;D;D
Sift4G	Benign	0.074	T;T;T;T
Polyphen		0.99	D;D;.;.
Vest4		0.74
MutPred		0.56		Loss of MoRF binding (P = 0.0573);.;.;Loss of MoRF binding (P = 0.0573);
MVP		0.94
MPC		1.0
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.67
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs137852682; hg19: chr3-184071575;