rs2280663

Variant names:

• chr7-143316199-C-A
• rs2280663
• NM_000083.3:c.-14C>A

Your query was ambiguous. Multiple possible variants found:

• chr7-143316199-C-A
• chr7-143316199-C-G
• chr7-143316199-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000083.3(CLCN1):​c.-14C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (157 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLCN1 NM_000083.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.11
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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=-0.94).
• BP6: Variant 7-143316199-C-A is Benign according to our data. Variant chr7-143316199-C-A is described in ClinVar as Benign. ClinVar VariationId is 383612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000083.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	NM_000083.3	MANE Select	c.-14C>A		5_prime_UTR	Exon 1 of 23	NP_000074.3	P35523
	CLCN1	NR_046453.2		n.89C>A		non_coding_transcript_exon	Exon 1 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.-14C>A		5_prime_UTR	Exon 1 of 23	ENSP00000339867.2	P35523
	CLCN1	ENST00000650516.2		c.-14C>A		5_prime_UTR	Exon 1 of 23	ENSP00000498052.2	A0A3B3IU72
	CLCN1	ENST00000958857.1		c.-14C>A		upstream_gene	N/A	ENSP00000628916.1

Frequencies

GnomAD3 genomes AF: 0.00467 AC: 690 AN: 147794 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0376

Gnomad ASJ AF: 0.000580

Gnomad EAS AF: 0.00832

Gnomad SAS AF: 0.00106

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000193

Gnomad OTH AF: 0.00987

GnomAD2 exomes AF: 0.0117 AC: 2883 AN: 246368 AF XY: 0.00922

Gnomad AFR exome AF: 0.000881

Gnomad AMR exome AF: 0.0763

Gnomad ASJ exome AF: 0.000702

Gnomad EAS exome AF: 0.00704

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.0111

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00291 AC: 4226 AN: 1453328 Hom.: 157 Cov.: 32 AF XY: 0.00261 AC XY: 1891 AN XY: 723312

African (AFR) AF: 0.000569 AC: 19 AN: 33380

American (AMR) AF: 0.0726 AC: 3243 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.000575 AC: 15 AN: 26094

East Asian (EAS) AF: 0.0151 AC: 600 AN: 39650

South Asian (SAS) AF: 0.000883 AC: 76 AN: 86090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51006

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5762

European-Non Finnish (NFE) AF: 0.000108 AC: 120 AN: 1106510

Other (OTH) AF: 0.00246 AC: 148 AN: 60164

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00466 AC: 689 AN: 147886 Hom.: 11 Cov.: 32 AF XY: 0.00493 AC XY: 355 AN XY: 72048

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00127 AC: 50 AN: 39354

American (AMR) AF: 0.0375 AC: 557 AN: 14840

Ashkenazi Jewish (ASJ) AF: 0.000580 AC: 2 AN: 3446

East Asian (EAS) AF: 0.00834 AC: 42 AN: 5038

South Asian (SAS) AF: 0.00107 AC: 5 AN: 4690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000193 AC: 13 AN: 67184

Other (OTH) AF: 0.00977 AC: 20 AN: 2048

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000783 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.088
DANN	Benign	0.67
PhyloP100		-2.1
PromoterAI		0.0070	Neutral
Mutation Taster		=300/0	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: rs2280663; hg19: chr7-143013292;