chr7-143346256-C-T

Variant names:

• chr7-143346256-C-T
• rs74824159
• NM_000083.3:c.2284+5C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000083.3(CLCN1):​c.2284+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 1,590,352 control chromosomes in the GnomAD database, including 591 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.017 (32 hom., cov: 31)
  • Exomes 𝑓: 0.025 (559 hom.)
• Consequence: CLCN1 NM_000083.3 splice_region, intron
• Scores: Splicing: ADA: 0.001404
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: -0.313
• Publications: 8 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 7-143346256-C-T is Benign according to our data. Variant chr7-143346256-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 252462.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0171 (2605/152228) while in subpopulation NFE AF = 0.0281 (1913/68020). AF 95% confidence interval is 0.0271. There are 32 homozygotes in GnomAd4. There are 1143 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 AD,AR gene

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.2284+5C>T		splice_region intron	N/A	NP_000074.3	P35523
	CLCN1	NR_046453.2		n.2239+5C>T		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.2284+5C>T		splice_region intron	N/A	ENSP00000339867.2	P35523
	CLCN1	ENST00000432192.6	TSL:1	n.*1569+5C>T		splice_region intron	N/A	ENSP00000395949.2	H7C0N6
	CLCN1	ENST00000650516.2		c.2284+5C>T		splice_region intron	N/A	ENSP00000498052.2	A0A3B3IU72

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2605 AN: 152110 Hom.: 32 Cov.: 31

Gnomad AFR AF: 0.00572

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00993

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0281

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0178 AC: 4457 AN: 250744 AF XY: 0.0183

Gnomad AFR exome AF: 0.00524

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.00984

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.00532

Gnomad NFE exome AF: 0.0288

Gnomad OTH exome AF: 0.0198

GnomAD4 exome AF: 0.0254 AC: 36510 AN: 1438124 Hom.: 559 Cov.: 31 AF XY: 0.0250 AC XY: 17947 AN XY: 716904

African (AFR) AF: 0.00489 AC: 161 AN: 32918

American (AMR) AF: 0.0143 AC: 641 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0111 AC: 288 AN: 25954

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39608

South Asian (SAS) AF: 0.00922 AC: 791 AN: 85752

European-Finnish (FIN) AF: 0.00748 AC: 396 AN: 52940

Middle Eastern (MID) AF: 0.0279 AC: 160 AN: 5726

European-Non Finnish (NFE) AF: 0.0301 AC: 32833 AN: 1090946

Other (OTH) AF: 0.0207 AC: 1232 AN: 59594

GnomAD4 genome AF: 0.0171 AC: 2605 AN: 152228 Hom.: 32 Cov.: 31 AF XY: 0.0154 AC XY: 1143 AN XY: 74430

African (AFR) AF: 0.00571 AC: 237 AN: 41520

American (AMR) AF: 0.0182 AC: 279 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5154

South Asian (SAS) AF: 0.00994 AC: 48 AN: 4828

European-Finnish (FIN) AF: 0.00405 AC: 43 AN: 10614

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0281 AC: 1913 AN: 68020

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.0220 Hom.: 14

Bravo AF: 0.0175

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0291

EpiControl AF: 0.0302

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Batten-Turner congenital myopathy (1)
-	1	-	Congenital myotonia, autosomal recessive form (1)
-	-	1	Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.6
DANN	Benign	0.87
PhyloP100		-0.31
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
dbscSNV1_RF	Benign	0.018
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: rs74824159; hg19: chr7-143043349;