rs80356706

Positions:

chr7-143351793-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_000083.3(CLCN1):c.2795C>T(p.Pro932Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,614,150 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:3O:1

Conservation

PhyloP100: 1.22

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3 linkuse as main transcript	c.2795C>T	p.Pro932Leu	missense_variant	23/23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2 linkuse as main transcript	n.2750C>T		non_coding_transcript_exon_variant	22/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7 linkuse as main transcript	c.2795C>T	p.Pro932Leu	missense_variant	23/23	1	NM_000083.3	ENSP00000339867	P4
CLCN1	ENST00000650516.2 linkuse as main transcript	c.2795C>T	p.Pro932Leu	missense_variant	23/23			ENSP00000498052	A2

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000128

AC:

AN:

250476

Hom.:

AF XY:

0.0000664

AC XY:

AN XY:

135508

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.000260

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:

0.0000376

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000956

Gnomad4 AMR exome

AF:

0.000201

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:

0.00000180

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000341

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000750

Hom.:

Bravo

AF:

0.000389

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2020	Functional studies indicate P932L results in reduced surface expression of CLCN1 protein (Macias et al., 2007); Functional studies demonstrate that P932L results in nearly wildtype chloride currents (Simpson et al., 2004); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19917643, 27653901, 18263754, 11933197, 15241802, 11113225, 12566541, 15786415, 23739125, 15311340, 29935101, 17107341, 32117034) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 13, 2022	- -

Congenital myotonia, autosomal recessive form

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 12, 2000

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 932 of the CLCN1 protein (p.Pro932Leu). This variant is present in population databases (rs80356706, gnomAD 0.1%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 11113225, 23739125). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17533). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CLCN1 protein function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CLCN1 function (PMID: 15241802, 17107341). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Batten-Turner congenital myopathy

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.57

DEOGEN2

Benign

0.12

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.73

M_CAP

Benign

0.063

MetaRNN

Uncertain

0.69

MetaSVM

Benign

-0.42

MutationAssessor

Benign

0.51

MutationTaster

Benign

0.0000071

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.48

Sift

Uncertain

0.024

Sift4G

Benign

0.34

Polyphen

0.0010

Vest4

0.70

MVP

0.90

MPC

0.19

ClinPred

0.0088

GERP RS

3.7

Varity_R

0.040

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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