rs1554439817

Positions:

• chr7-143350387-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000083.3(CLCN1):​c.2419C>T​(p.Gln807Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLCN1 NM_000083.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.97

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-143350387-C-T is Pathogenic according to our data. Variant chr7-143350387-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 462830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143350387-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN1	NM_000083.3	c.2419C>T	p.Gln807Ter	stop_gained	21/23	ENST00000343257.7
CLCN1	NR_046453.2	n.2374C>T		non_coding_transcript_exon_variant	20/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN1	ENST00000343257.7	c.2419C>T	p.Gln807Ter	stop_gained	21/23	1	NM_000083.3	P4
CLCN1	ENST00000432192.6	c.*1704C>T		3_prime_UTR_variant, NMD_transcript_variant	21/23	1
CLCN1	ENST00000650516.2	c.2419C>T	p.Gln807Ter	stop_gained	21/23			A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jun 28, 2019

- -

Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2016

This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal at codon 807 (p.Gln807*) of the CLCN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLCN1 are known to be pathogenic. This particular variant has been reported in the literature in two individuals affected with myotonia congenita (PMID: 11933197, 23739125). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.79	D
MutationTaster	Benign	1.0	A
Vest4		0.87
GERP RS		2.6

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: rs1554439817; hg19: chr7-143047480;