rs147317366

Positions:

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_000083.3(CLCN1):c.663G>A(p.Ala221=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00511 in 1,614,214 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A221A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0047 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0052 ( 34 hom. )

Consequence

CLCN1
NM_000083.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -3.03

Variant links:

Genes affected

CLCN1 (HGNC:2019): (chloride voltage-gated channel 1) The CLCN family of voltage-dependent chloride channel genes comprises nine members (CLCN1-7, Ka and Kb) which demonstrate quite diverse functional characteristics while sharing significant sequence homology. The protein encoded by this gene regulates the electric excitability of the skeletal muscle membrane. Mutations in this gene cause two forms of inherited human muscle disorders: recessive generalized myotonia congenita (Becker) and dominant myotonia (Thomsen). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

CLCN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 7-143321815-G-A is Benign according to our data. Variant chr7-143321815-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 359104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.03 with no splicing effect.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3 linkuse as main transcript	c.663G>A	p.Ala221=	synonymous_variant	5/23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2 linkuse as main transcript	n.765G>A		non_coding_transcript_exon_variant	5/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7 linkuse as main transcript	c.663G>A	p.Ala221=	synonymous_variant	5/23	1	NM_000083.3	ENSP00000339867	P4

Frequencies

GnomAD3 genomes

AF:

0.00469

AC:

714

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00766

Gnomad FIN

AF:

0.0174

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00517

Gnomad OTH

AF:

0.00573

GnomAD3 exomes

AF:

0.00581

AC:

1461

AN:

251338

Hom.:

AF XY:

0.00610

AC XY:

829

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.0113

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0111

Gnomad FIN exome

AF:

0.0142

Gnomad NFE exome

AF:

0.00522

Gnomad OTH exome

AF:

0.00685

GnomAD4 exome

AF:

0.00515

AC:

7532

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00540

AC XY:

3927

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.00177

Gnomad4 ASJ exome

AF:

0.0112

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0109

Gnomad4 FIN exome

AF:

0.0130

Gnomad4 NFE exome

AF:

0.00459

Gnomad4 OTH exome

AF:

0.00565

GnomAD4 genome

AF:

0.00469

AC:

714

AN:

152350

Hom.:

Cov.:

AF XY:

0.00518

AC XY:

386

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00767

Gnomad4 FIN

AF:

0.0174

Gnomad4 NFE

AF:

0.00517

Gnomad4 OTH

AF:

0.00567

Alfa

AF:

0.00412

Hom.:

Bravo

AF:

0.00368

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.00611

EpiControl

AF:

0.00610

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	CLCN1: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	research	Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	-	The c.663G>A (p.(Ala221=)) variant was found in a heterozygous state in 2 Slovak patients with Myotonia congenita, both of whom carried 2 other Likely Pathogenic variants. It is a silent variant that has a population frequency not consistent with the disease (gnomAD ExomesVersion: 4.0 frequency f = 0.00515). Interestingly, both mentioned patients also carried heterozygous CLCN1 splicing variant c.2364+2T>C, indicating its inheritance in cis with c.663G>A. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 09, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Batten-Turner congenital myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

CLCN1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 27, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.23

DANN

Benign

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over