rs940864

Positions:

• chr7-143342218-A-G
• chr7-143342218-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000083.3(CLCN1):​c.1796+76A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.416 in 1,515,792 control chromosomes in the GnomAD database, including 133,522 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15213 hom., cov: 32)
  • Exomes 𝑓: 0.41 (118309 hom.)
• Consequence: CLCN1 NM_000083.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0860

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 7-143342218-A-G is Benign according to our data. Variant chr7-143342218-A-G is described in ClinVar as [Benign]. Clinvar id is 1255317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCN1	NM_000083.3	c.1796+76A>G		intron_variant		ENST00000343257.7	NP_000074.3
CLCN1	NR_046453.2	n.1751+76A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCN1	ENST00000343257.7	c.1796+76A>G		intron_variant		1	NM_000083.3	ENSP00000339867.2
CLCN1	ENST00000432192.6	n.*1081+76A>G		intron_variant		1		ENSP00000395949.2
CLCN1	ENST00000650516.2	c.1796+76A>G		intron_variant				ENSP00000498052.2

Frequencies

GnomAD3 genomes AF: 0.439 AC: 66641 AN: 151864 Hom.: 15179 Cov.: 32

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.513

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.450

GnomAD4 exome AF: 0.414 AC: 564070 AN: 1363810 Hom.: 118309 Cov.: 21 AF XY: 0.414 AC XY: 282596 AN XY: 682758

Gnomad4 AFR exome AF: 0.565

Gnomad4 AMR exome AF: 0.312

Gnomad4 ASJ exome AF: 0.501

Gnomad4 EAS exome AF: 0.305

Gnomad4 SAS exome AF: 0.419

Gnomad4 FIN exome AF: 0.388

Gnomad4 NFE exome AF: 0.415

Gnomad4 OTH exome AF: 0.428

GnomAD4 genome AF: 0.439 AC: 66731 AN: 151982 Hom.: 15213 Cov.: 32 AF XY: 0.433 AC XY: 32198 AN XY: 74284

Gnomad4 AFR AF: 0.561

Gnomad4 AMR AF: 0.338

Gnomad4 ASJ AF: 0.513

Gnomad4 EAS AF: 0.269

Gnomad4 SAS AF: 0.409

Gnomad4 FIN AF: 0.372

Gnomad4 NFE AF: 0.412

Gnomad4 OTH AF: 0.446

Alfa AF: 0.430 Hom.: 2831

Bravo AF: 0.441

Asia WGS AF: 0.353 AC: 1233 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.2
DANN	Benign	0.67

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: rs940864; hg19: chr7-143039311; COSMIC: COSV58369501;