NM_000083.3:c.2364+2T>C

Variant names:

• chr7-143346660-T-C
• NM_000083.3:c.2364+2T>C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000083.3(CLCN1):​c.2364+2T>C variant causes a splice donor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLCN1 NM_000083.3 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.29

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-143346660-T-C is Pathogenic according to our data. Variant chr7-143346660-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3233338.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.2364+2T>C		splice_donor_variant, intron_variant	Intron 19 of 22	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.2319+2T>C		splice_donor_variant, intron_variant	Intron 18 of 21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.2364+2T>C		splice_donor_variant, intron_variant	Intron 19 of 22	1	NM_000083.3	ENSP00000339867.2
CLCN1	ENST00000432192.6	n.*1649+2T>C		splice_donor_variant, intron_variant	Intron 19 of 22	1		ENSP00000395949.2
CLCN1	ENST00000650516.2	c.2364+2T>C		splice_donor_variant, intron_variant	Intron 19 of 22			ENSP00000498052.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

-

Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The c.2364+2T>C (p.?) variant was found in a heterozygous state in 2 Slovak patients with Myotonia congenita, who carried other Likely pathogenic variants, namely, the first patient carried also the variant c.1437_1450del, while the second one two CLCN1 variants known to be inherited in cis [c.905A>G; c.1295C>A]. The c.2364+2T>C variant is listed as a disease-causing in the HGMD database (CS1514222), it is not reported in dbSNP, but it has been published previously (PMID: 26260254). GnomAD Exomes Version: 4.0 indicates the frequency of f = 0.0000315. Another variant has been reported to affect the same nucleotide position, c.2364+2T>A (rs886041384), present also as a disease-causing in the HGMD database (CS971661), and published in PMID: 10215406. In gnomAD ExomesVersion: 4.0 it was found with f = 0.00000549. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	26
DANN	Uncertain	0.99
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.88	D
GERP RS		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.94		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-143043753;