rs114350071

Positions:

• chr3-184352435-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004366.6(CLCN2):​c.2271+8T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00238 in 1,613,310 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (24 hom.)
• Consequence: CLCN2 NM_004366.6 splice_region, intron
• Scores: Splicing: ADA: 0.00001746
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.10

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 3-184352435-A-C is Benign according to our data. Variant chr3-184352435-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 445441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-184352435-A-C is described in Lovd as [Benign]. Variant chr3-184352435-A-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00973 (1482/152300) while in subpopulation AFR AF= 0.0316 (1315/41552). AF 95% confidence interval is 0.0302. There are 22 homozygotes in gnomad4. There are 707 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1482 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN2	NM_004366.6	c.2271+8T>G		splice_region_variant, intron_variant		ENST00000265593.9	NP_004357.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN2	ENST00000265593.9	c.2271+8T>G		splice_region_variant, intron_variant		1	NM_004366.6	ENSP00000265593	P1

Frequencies

GnomAD3 genomes AF: 0.00971 AC: 1478 AN: 152182 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00347 AC: 868 AN: 249922 Hom.: 10 AF XY: 0.00275 AC XY: 372 AN XY: 135400

Gnomad AFR exome AF: 0.0337

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000393

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000842

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00162 AC: 2364 AN: 1461010 Hom.: 24 Cov.: 33 AF XY: 0.00151 AC XY: 1100 AN XY: 726794

Gnomad4 AFR exome AF: 0.0331

Gnomad4 AMR exome AF: 0.00320

Gnomad4 ASJ exome AF: 0.00995

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000395

Gnomad4 FIN exome AF: 0.0000757

Gnomad4 NFE exome AF: 0.000469

Gnomad4 OTH exome AF: 0.00388

GnomAD4 genome AF: 0.00973 AC: 1482 AN: 152300 Hom.: 22 Cov.: 32 AF XY: 0.00949 AC XY: 707 AN XY: 74478

Gnomad4 AFR AF: 0.0316

Gnomad4 AMR AF: 0.00431

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00689 Hom.: 5

Bravo AF: 0.0113

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 02, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

Familial hyperaldosteronism type II;C2750893:Epilepsy, idiopathic generalized, susceptibility to, 11;C4554120:Leukoencephalopathy with mild cerebellar ataxia and white matter edema Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.27
DANN	Benign	0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0
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: rs114350071; hg19: chr3-184070223;