7-143320714-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000083.3(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 NM_000083.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.18

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]

ACMG classification

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 NM_000083.3
• 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	UniProt
CLCN1	NM_000083.3	c.352G>T	p.Gly118Trp	missense_variant	3/23	ENST00000343257.7
CLCN1	NR_046453.2	n.454G>T		non_coding_transcript_exon_variant	3/22

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.984 AC: 149559 AN: 152008 Hom.: 73590 Cov.: 29

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

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.: 39 AF XY: 0.977 AC XY: 710223 AN XY: 727110

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.: 29 AF XY: 0.985 AC XY: 73258 AN XY: 74354

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:7

Revision: criteria provided, multiple submitters, no conflicts

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

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Congenital myotonia, autosomal recessive form Benign:2

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

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	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	17
Dann	Benign	0.92
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	5.6e-7	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.98	P
PrimateAI	Uncertain	0.75	T
Polyphen		0.0	.;B
Vest4		0.091
MPC		0.22
ClinPred		0.022	T
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

Other links and lift over

dbSNP: rs10282312; hg19: chr7-143017807;