rs118066140

Positions:

chr7-143330817-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PM5BP4_StrongBP6BS2

The ENST00000343257.7(CLCN1):c.899G>A(p.Arg300Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 1,614,162 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R300W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0046 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0073 ( 45 hom. )

Consequence

CLCN1
ENST00000343257.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 8.13

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 -5 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000343257.7

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-143330816-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.016606092).

BP6

Variant 7-143330817-G-A is Benign according to our data. Variant chr7-143330817-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252463.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1, Likely_benign=3}. Variant chr7-143330817-G-A is described in Lovd as [Pathogenic]. Variant chr7-143330817-G-A is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 45 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3 linkuse as main transcript	c.899G>A	p.Arg300Gln	missense_variant	8/23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2 linkuse as main transcript	n.1004G>A		non_coding_transcript_exon_variant	8/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7 linkuse as main transcript	c.899G>A	p.Arg300Gln	missense_variant	8/23	1	NM_000083.3	ENSP00000339867	P4

Frequencies

GnomAD3 genomes

AF:

0.00459

AC:

698

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00167

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00622

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00783

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00475

AC:

1195

AN:

251402

Hom.:

AF XY:

0.00498

AC XY:

677

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00205

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.00480

Gnomad FIN exome

AF:

0.00115

Gnomad NFE exome

AF:

0.00785

Gnomad OTH exome

AF:

0.00456

GnomAD4 exome

AF:

0.00734

AC:

10728

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00729

AC XY:

5303

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00235

Gnomad4 ASJ exome

AF:

0.000880

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.00512

Gnomad4 FIN exome

AF:

0.00180

Gnomad4 NFE exome

AF:

0.00871

Gnomad4 OTH exome

AF:

0.00527

GnomAD4 genome

AF:

0.00458

AC:

698

AN:

152286

Hom.:

Cov.:

AF XY:

0.00422

AC XY:

314

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00166

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00622

Gnomad4 FIN

AF:

0.00122

Gnomad4 NFE

AF:

0.00783

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00643

Hom.:

Bravo

AF:

0.00439

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00826

AC:

ExAC

AF:

0.00464

AC:

564

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00709

EpiControl

AF:

0.00848

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 06, 2015	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 02, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CLCN1: PP3, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 16, 2018	- -

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

Benign:2

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.899G>A (p.(Arg300Gln)) variant was found in a heterozygous state in 2 Slovak patients with Myotonia congenita: the first one carried another 2 Likely Pathogenic variants: c.1231G>T and C2680C>T; while in the second one, no other Pathogenic or Likely pathogenic variants were found. GnomAD Exomes Version: 4.0 indicates the frequency of f = 0.00734. This variant has been reported in HGMD database CM940284. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Congenital myotonia, autosomal recessive form

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Sep 21, 2017

- -

Batten-Turner congenital myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

0.0053

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

.;D

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.017

T;T

MetaSVM

Uncertain

0.79

MutationAssessor

Uncertain

2.9

.;M

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.7

.;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.0030

.;D

Polyphen

1.0

.;D

Vest4

0.79

MVP

0.98

MPC

0.68

ClinPred

0.023

GERP RS

3.7

Varity_R

0.92

gMVP

0.77

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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