7-143342417-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 3P and 12B. PM5PP3BP6_Very_StrongBS2

The NM_000083.3(CLCN1):c.1842G>C(p.Lys614Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 1,614,116 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K614M) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 14 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.91

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 -9 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-143342416-A-T is described in Lovd as [Pathogenic].

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 7-143342417-G-C is Benign according to our data. Variant chr7-143342417-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 359114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143342417-G-C is described in Lovd as [Pathogenic]. Variant chr7-143342417-G-C is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3 link	c.1842G>C	p.Lys614Asn	missense_variant	Exon 16 of 23	ENST00000343257.7	NP_000074.3	P35523
CLCN1	NR_046453.2 link	n.1797G>C		non_coding_transcript_exon_variant	Exon 15 of 22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLCN1	ENST00000343257.7 link	c.1842G>C	p.Lys614Asn	missense_variant	Exon 16 of 23	1	NM_000083.3	ENSP00000339867.2	P35523
CLCN1	ENST00000432192.6 link	n.*1127G>C		non_coding_transcript_exon_variant	Exon 16 of 23	1		ENSP00000395949.2	H7C0N6
CLCN1	ENST00000432192.6 link	n.*1127G>C		3_prime_UTR_variant	Exon 16 of 23	1		ENSP00000395949.2	H7C0N6
CLCN1	ENST00000650516.2 link	c.1842G>C	p.Lys614Asn	missense_variant	Exon 16 of 23			ENSP00000498052.2	A0A3B3IU72

Frequencies

GnomAD3 genomes

AF:

0.00183

AC:

278

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00357

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.00147

AC:

369

AN:

251468

Hom.:

AF XY:

0.00146

AC XY:

198

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.000785

Gnomad NFE exome

AF:

0.00278

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00339

AC:

4950

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00318

AC XY:

2312

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.000655

Gnomad4 NFE exome

AF:

0.00425

Gnomad4 OTH exome

AF:

0.00224

GnomAD4 genome

AF:

0.00183

AC:

278

AN:

152246

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

111

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00357

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.00163

Hom.:

Bravo

AF:

0.00186

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00137

AC:

167

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00251

EpiControl

AF:

0.00320

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 09, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25179549, 19185184, 12661046, 29606556) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Jul 01, 2024

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Batten-Turner congenital myopathy

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 12, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

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

Benign:1

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.71

M_CAP

Benign

0.057

MetaRNN

Benign

0.022

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.1

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.41

Sift

Uncertain

0.015

Sift4G

Benign

0.11

Polyphen

0.71

Vest4

0.45

MutPred

0.62

Loss of ubiquitination at K614 (P = 0.0297);

MVP

0.89

MPC

0.47

ClinPred

0.034

GERP RS

4.9

Varity_R

0.33

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.65

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.65

Position offset: 11

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