chr7-143332781-G-A

Position:

chr7-143332781-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000083.3(CLCN1):c.1309G>A(p.Ala437Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,614,042 control chromosomes in the GnomAD database, including 171 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0093 ( 12 hom., cov: 32)

Exomes 𝑓: 0.012 ( 159 hom. )

Consequence

CLCN1
NM_000083.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.259

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0034332275).

BP6

Variant 7-143332781-G-A is Benign according to our data. Variant chr7-143332781-G-A is described in ClinVar as [Benign]. Clinvar id is 359109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143332781-G-A is described in Lovd as [Benign]. Variant chr7-143332781-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 12 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3 linkuse as main transcript	c.1309G>A	p.Ala437Thr	missense_variant	12/23	ENST00000343257.7	NP_000074.3	P35523
CLCN1	NR_046453.2 linkuse as main transcript	n.1356+278G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CLCN1	ENST00000343257.7 linkuse as main transcript	c.1309G>A	p.Ala437Thr	missense_variant	12/23	1	NM_000083.3	ENSP00000339867.2	P35523
CLCN1	ENST00000432192.6 linkuse as main transcript	n.*594G>A		non_coding_transcript_exon_variant	12/23	1		ENSP00000395949.2	H7C0N6
CLCN1	ENST00000432192.6 linkuse as main transcript	n.*594G>A		3_prime_UTR_variant	12/23	1		ENSP00000395949.2	H7C0N6
CLCN1	ENST00000650516.2 linkuse as main transcript	c.1309G>A	p.Ala437Thr	missense_variant	12/23			ENSP00000498052.2	A0A3B3IU72

Frequencies

GnomAD3 genomes

AF:

0.00929

AC:

1414

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00290

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0114

Gnomad ASJ

AF:

0.0556

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00539

Gnomad FIN

AF:

0.00443

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0120

Gnomad OTH

AF:

0.0129

GnomAD3 exomes

AF:

0.0109

AC:

2746

AN:

251460

Hom.:

AF XY:

0.0112

AC XY:

1526

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00252

Gnomad AMR exome

AF:

0.00757

Gnomad ASJ exome

AF:

0.0527

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00617

Gnomad FIN exome

AF:

0.00457

Gnomad NFE exome

AF:

0.0133

Gnomad OTH exome

AF:

0.0178

GnomAD4 exome

AF:

0.0124

AC:

18174

AN:

1461792

Hom.:

159

Cov.:

AF XY:

0.0123

AC XY:

8954

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00236

Gnomad4 AMR exome

AF:

0.00863

Gnomad4 ASJ exome

AF:

0.0506

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00653

Gnomad4 FIN exome

AF:

0.00464

Gnomad4 NFE exome

AF:

0.0132

Gnomad4 OTH exome

AF:

0.0140

GnomAD4 genome

AF:

0.00929

AC:

1415

AN:

152250

Hom.:

Cov.:

AF XY:

0.00875

AC XY:

651

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00294

Gnomad4 AMR

AF:

0.0114

Gnomad4 ASJ

AF:

0.0556

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00560

Gnomad4 FIN

AF:

0.00443

Gnomad4 NFE

AF:

0.0120

Gnomad4 OTH

AF:

0.0128

Alfa

AF:

0.0135

Hom.:

Bravo

AF:

0.00999

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0137

AC:

118

ExAC

AF:

0.0111

AC:

1346

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0148

EpiControl

AF:

0.0155

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 04, 2016	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, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2021	- -

Batten-Turner congenital myopathy

Benign:1

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

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.030

DANN

Benign

0.73

DEOGEN2

Benign

0.34

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.33

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.81

MutationAssessor

Benign

0.59

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.19

REVEL

Benign

0.21

Sift

Benign

0.57

Sift4G

Benign

0.65

Polyphen

0.0020

Vest4

0.11

MPC

0.18

ClinPred

0.0024

GERP RS

-11

Varity_R

0.045

gMVP

0.49

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