rs144612641

Positions:

chr7-143346201-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000083.3(CLCN1):c.2234A>G(p.Asn745Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000559 in 1,613,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00056 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 5.51

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 Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11425492).

BP6

Variant 7-143346201-A-G is Benign according to our data. Variant chr7-143346201-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447060.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3 linkuse as main transcript	c.2234A>G	p.Asn745Ser	missense_variant	18/23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2 linkuse as main transcript	n.2189A>G		non_coding_transcript_exon_variant	17/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CLCN1	ENST00000343257.7 linkuse as main transcript	c.2234A>G	p.Asn745Ser	missense_variant	18/23	1	NM_000083.3	ENSP00000339867	P4
CLCN1	ENST00000432192.6 linkuse as main transcript	c.*1519A>G		3_prime_UTR_variant, NMD_transcript_variant	18/23	1		ENSP00000395949
CLCN1	ENST00000650516.2 linkuse as main transcript	c.2234A>G	p.Asn745Ser	missense_variant	18/23			ENSP00000498052	A2

Frequencies

GnomAD3 genomes

AF:

0.000500

AC:

AN:

151980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000653

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000573

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.000426

AC:

107

AN:

251402

Hom.:

AF XY:

0.000294

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.000652

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000457

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000562

AC:

821

AN:

1461752

Hom.:

Cov.:

AF XY:

0.000517

AC XY:

376

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.000554

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000632

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.000533

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.000525

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.000771

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000573

Gnomad4 OTH

AF:

0.000476

Alfa

AF:

0.000769

Hom.:

Bravo

AF:

0.000552

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000313

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 30, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 27, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Batten-Turner congenital myopathy

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.80

M_CAP

Benign

0.051

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.37

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

0.78

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.80

REVEL

Uncertain

0.33

Sift

Benign

0.53

Sift4G

Benign

0.84

Polyphen

0.97

Vest4

0.44

MVP

0.90

MPC

0.43

ClinPred

0.034

GERP RS

4.3

Varity_R

0.090

gMVP

0.38

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