7-143320714-G-T

Position:

chr7-143320714-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The ENST00000343257.7(CLCN1):c.352G>T(p.Gly118Trp) variant causes a missense change. The variant allele was found at a frequency of 0.977 in 1,613,664 control chromosomes in the GnomAD database, including 769,979 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G118G) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.98 ( 73648 hom., cov: 29)

Exomes 𝑓: 0.98 ( 696331 hom. )

Consequence

CLCN1
ENST00000343257.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 6.18

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a helix (size 34) in uniprot entity CLCN1_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) in ENST00000343257.7

BP4

Computational evidence support a benign effect (MetaRNN=5.607244E-7).

BP6

Variant 7-143320714-G-T is Benign according to our data. Variant chr7-143320714-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 802378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143320714-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.987 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3 linkuse as main transcript	c.352G>T	p.Gly118Trp	missense_variant	3/23	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2 linkuse as main transcript	n.454G>T		non_coding_transcript_exon_variant	3/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CLCN1	ENST00000343257.7 linkuse as main transcript	c.352G>T	p.Gly118Trp	missense_variant	3/23	1	NM_000083.3	ENSP00000339867	P4
CLCN1	ENST00000432192.6 linkuse as main transcript	c.121G>T	p.Gly41Trp	missense_variant, NMD_transcript_variant	2/23	1		ENSP00000395949
CLCN1	ENST00000650516.2 linkuse as main transcript	c.352G>T	p.Gly118Trp	missense_variant	3/23			ENSP00000498052	A2

Frequencies

GnomAD3 genomes

AF:

0.984

AC:

149559

AN:

152008

Hom.:

73590

Cov.:

show subpopulations

Gnomad AFR

AF:

0.996

Gnomad AMI

AF:

0.897

Gnomad AMR

AF:

0.991

Gnomad ASJ

AF:

0.983

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.998

Gnomad FIN

AF:

0.985

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

0.974

Gnomad OTH

AF:

0.990

GnomAD3 exomes

AF:

0.985

AC:

247777

AN:

251494

Hom.:

122083

AF XY:

0.985

AC XY:

133910

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.996

Gnomad AMR exome

AF:

0.995

Gnomad ASJ exome

AF:

0.979

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.998

Gnomad FIN exome

AF:

0.980

Gnomad NFE exome

AF:

0.976

Gnomad OTH exome

AF:

0.985

GnomAD4 exome

AF:

0.976

AC:

1426547

AN:

1461538

Hom.:

696331

Cov.:

AF XY:

0.977

AC XY:

710223

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.997

Gnomad4 AMR exome

AF:

0.994

Gnomad4 ASJ exome

AF:

0.980

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.998

Gnomad4 FIN exome

AF:

0.979

Gnomad4 NFE exome

AF:

0.972

Gnomad4 OTH exome

AF:

0.978

GnomAD4 genome

AF:

0.984

AC:

149676

AN:

152126

Hom.:

73648

Cov.:

AF XY:

0.985

AC XY:

73258

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.996

Gnomad4 AMR

AF:

0.991

Gnomad4 ASJ

AF:

0.983

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.998

Gnomad4 FIN

AF:

0.985

Gnomad4 NFE

AF:

0.974

Gnomad4 OTH

AF:

0.991

Alfa

AF:

0.977

Hom.:

63527

Bravo

AF:

0.985

TwinsUK

AF:

0.974

AC:

3613

ALSPAC

AF:

0.972

AC:

3748

ESP6500AA

AF:

0.995

AC:

4385

ESP6500EA

AF:

0.975

AC:

8385

ExAC

AF:

0.986

AC:

119721

Asia WGS

AF:

0.999

AC:

3474

AN:

3478

EpiCase

AF:

0.977

EpiControl

AF:

0.981

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	research	Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	-	Almost all patients from our cohort were homozygous for this variant c.352G>T (p.(Gly118Trp)), indicating that T represents a wild-type allele. We identified only one patient homozygous for allele G, who, however, was homozygous also for the Likely Pathogenic variant c.959A>C (p.(Ala320Val)). Only according to the publication PMID: 23152584, c.352G>T variant can have a weak effect. -

Congenital myotonia, autosomal recessive form

Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Congenital myotonia, autosomal dominant form

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.038

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.14

.;T

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.72

T;T

MetaRNN

Benign

5.6e-7

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-3.1

.;N

MutationTaster

Benign

0.98

PrimateAI

Uncertain

0.75

PROVEAN

Benign

.;N

REVEL

Uncertain

0.29

Sift

Benign

1.0

.;T

Sift4G

Benign

1.0

.;T

Polyphen

0.0

.;B

Vest4

0.091

MPC

0.22

ClinPred

0.022

GERP RS

5.0

Varity_R

0.32

gMVP

0.78

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