rs10249881

Positions:

• chr7-143348309-G-A

Variant summary

Our verdict is Benign. Variant got -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

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 -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/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.2403+1360G>A		intron_variant		ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.2358+1360G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.2403+1360G>A		intron_variant		1	NM_000083.3	ENSP00000339867	P4
CLCN1	ENST00000432192.6	c.*1688+1360G>A		intron_variant, NMD_transcript_variant		1		ENSP00000395949
CLCN1	ENST00000650516.2	c.2403+1360G>A		intron_variant				ENSP00000498052	A2

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

Gnomad4 AFR AF: 0.479

Gnomad4 AMR AF: 0.325

Gnomad4 ASJ AF: 0.517

Gnomad4 EAS AF: 0.267

Gnomad4 SAS AF: 0.409

Gnomad4 FIN AF: 0.370

Gnomad4 NFE AF: 0.410

Gnomad4 OTH AF: 0.427

Alfa AF: 0.414 Hom.: 8295

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

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: rs10249881; hg19: chr7-143045402;