7-143346186-C-G

Position:

chr7-143346186-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000083.3(CLCN1):c.2219C>G(p.Ser740Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000719 in 1,613,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.205

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:

CLCN1 (HGNC:):

CLCN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020555109).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3 linkuse as main transcript	c.2219C>G	p.Ser740Cys	missense_variant	18/23	ENST00000343257.7	NP_000074.3	P35523
CLCN1	NR_046453.2 linkuse as main transcript	n.2174C>G		non_coding_transcript_exon_variant	17/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CLCN1	ENST00000343257.7 linkuse as main transcript	c.2219C>G	p.Ser740Cys	missense_variant	18/23	1	NM_000083.3	ENSP00000339867.2	P35523
CLCN1	ENST00000432192.6 linkuse as main transcript	n.*1504C>G		non_coding_transcript_exon_variant	18/23	1		ENSP00000395949.2	H7C0N6
CLCN1	ENST00000432192.6 linkuse as main transcript	n.*1504C>G		3_prime_UTR_variant	18/23	1		ENSP00000395949.2	H7C0N6
CLCN1	ENST00000650516.2 linkuse as main transcript	c.2219C>G	p.Ser740Cys	missense_variant	18/23			ENSP00000498052.2	A0A3B3IU72

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000127

AC:

AN:

251412

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000472

AC:

AN:

1461460

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727080

show subpopulations

Gnomad4 AFR exome

AF:

0.00179

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000309

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000453

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000988

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2024	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 -

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

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2023

The c.2219C>G (p.S740C) alteration is located in exon 18 (coding exon 18) of the CLCN1 gene. This alteration results from a C to G substitution at nucleotide position 2219, causing the serine (S) at amino acid position 740 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.21

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.65

M_CAP

Benign

0.045

MetaRNN

Benign

0.021

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.90

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.7

REVEL

Benign

0.20

Sift

Benign

0.070

Sift4G

Benign

0.12

Polyphen

0.53

Vest4

0.19

MVP

0.87

MPC

0.30

ClinPred

0.016

GERP RS

2.4

Varity_R

0.092

gMVP

0.39

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