3-184346710-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_004366.6(CLCN2):c.2593A>C(p.Ser865Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLCN2 NM_004366.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 4.13

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]

FAM131A (HGNC:28308): (family with sequence similarity 131 member A)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-184346710-T-G is Pathogenic according to our data. Variant chr3-184346710-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 441168.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27842432).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN2	NM_004366.6	c.2593A>C	p.Ser865Arg	missense_variant	24/24	ENST00000265593.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN2	ENST00000265593.9	c.2593A>C	p.Ser865Arg	missense_variant	24/24	1	NM_004366.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Familial hyperaldosteronism type II Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 10, 2018	- -
Pathogenic, no assertion criteria provided	in vitro;research	Ute Scholl Laboratory, Heinrich Heine University Duesseldorf	Sep 25, 2017	Four independent occurrences of CLCN2 p.Arg172Gln, significant burden of rare variants in CLCN2 in early-onset primary aldosteronism (two de novo), localization of CLCN2 in adrenal zona glomerulosa, electrophysiologic impact of mutant channels and effect on aldosterone synthase expression -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.9	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.088	T;T;T;T
Sift4G	Benign	0.37	T;T;T;T
Polyphen		0.97	D;D;.;.
Vest4		0.26
MutPred		0.14		Gain of glycosylation at T867 (P = 0.0306);.;.;.;
MVP		0.94
MPC		0.87
ClinPred		0.81	D
GERP RS		5.5
Varity_R		0.25
gMVP		0.87

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: rs1553853557; hg19: chr3-184064498;