rs10249881

Variant names:

• chr7-143348309-G-A
• rs10249881
• NM_000083.3:c.2403+1360G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000083.3(CLCN1):​c.2403+1360G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 151,912 control chromosomes in the GnomAD database, including 13,271 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.41 (13271 hom., cov: 32)
• Consequence: CLCN1 NM_000083.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.497
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• myotonia congenita, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• myotonia congenita, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Thomsen and Becker disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.2403+1360G>A		intron_variant	Intron 20 of 22	ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.2358+1360G>A		intron_variant	Intron 19 of 21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.2403+1360G>A		intron_variant	Intron 20 of 22	1	NM_000083.3	ENSP00000339867.2
CLCN1	ENST00000432192.6	n.*1688+1360G>A		intron_variant	Intron 20 of 22	1		ENSP00000395949.2
CLCN1	ENST00000650516.2	c.2403+1360G>A		intron_variant	Intron 20 of 22			ENSP00000498052.2

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62838 AN: 151794 Hom.: 13246 Cov.: 32

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.517

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.410

Gnomad OTH AF: 0.430

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.414 AC: 62919 AN: 151912 Hom.: 13271 Cov.: 32 AF XY: 0.408 AC XY: 30319 AN XY: 74250

African (AFR) AF: 0.479 AC: 19825 AN: 41430

American (AMR) AF: 0.325 AC: 4971 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 1791 AN: 3466

East Asian (EAS) AF: 0.267 AC: 1378 AN: 5152

South Asian (SAS) AF: 0.409 AC: 1967 AN: 4808

European-Finnish (FIN) AF: 0.370 AC: 3897 AN: 10536

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.410 AC: 27866 AN: 67936

Other (OTH) AF: 0.427 AC: 900 AN: 2106

Alfa AF: 0.415 Hom.: 10248

Bravo AF: 0.414

Asia WGS AF: 0.346 AC: 1207 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.27
DANN	Benign	0.72
PhyloP100		-0.50
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10249881; hg19: chr7-143045402;