rs113839156

Variant names:

• chr7-143320660-C-T
• rs113839156
• NM_000083.3:c.302-4C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000083.3(CLCN1):​c.302-4C>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 0.00138 in 1,597,782 control chromosomes in the GnomAD database, including 31 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (18 hom., cov: 30)
  • Exomes 𝑓: 0.00075 (13 hom.)
• Consequence: CLCN1 NM_000083.3 splice_region, intron
• Scores: Splicing: ADA: 0.0008940
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.807
• Publications: 1 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 7-143320660-C-T is Benign according to our data. Variant chr7-143320660-C-T is described in ClinVar as Benign. ClinVar VariationId is 462843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00733 (1105/150778) while in subpopulation AFR AF = 0.0251 (1031/41000). AF 95% confidence interval is 0.0239. There are 18 homozygotes in GnomAd4. There are 521 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 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.302-4C>T		splice_region intron	N/A	NP_000074.3
	CLCN1	NR_046453.2		n.404-4C>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.302-4C>T		splice_region intron	N/A	ENSP00000339867.2
	CLCN1	ENST00000432192.6	TSL:1	n.68-4C>T		splice_region intron	N/A	ENSP00000395949.2
	CLCN1	ENST00000650516.2		c.302-4C>T		splice_region intron	N/A	ENSP00000498052.2

Frequencies

GnomAD3 genomes AF: 0.00727 AC: 1095 AN: 150662 Hom.: 18 Cov.: 30

Gnomad AFR AF: 0.0250

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00325

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000590

Gnomad OTH AF: 0.00868

GnomAD2 exomes AF: 0.00193 AC: 485 AN: 251438 AF XY: 0.00131

Gnomad AFR exome AF: 0.0252

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.000755 AC: 1092 AN: 1447004 Hom.: 13 Cov.: 32 AF XY: 0.000609 AC XY: 438 AN XY: 719532

African (AFR) AF: 0.0264 AC: 871 AN: 33050

American (AMR) AF: 0.00176 AC: 78 AN: 44260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25594

East Asian (EAS) AF: 0.00 AC: 0 AN: 38698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52080

Middle Eastern (MID) AF: 0.000880 AC: 5 AN: 5680

European-Non Finnish (NFE) AF: 0.0000426 AC: 47 AN: 1102172

Other (OTH) AF: 0.00152 AC: 90 AN: 59390

GnomAD4 genome AF: 0.00733 AC: 1105 AN: 150778 Hom.: 18 Cov.: 30 AF XY: 0.00708 AC XY: 521 AN XY: 73560

African (AFR) AF: 0.0251 AC: 1031 AN: 41000

American (AMR) AF: 0.00325 AC: 49 AN: 15090

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5086

South Asian (SAS) AF: 0.000210 AC: 1 AN: 4758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10298

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0000590 AC: 4 AN: 67790

Other (OTH) AF: 0.00859 AC: 18 AN: 2096

Alfa AF: 0.00352 Hom.: 9

Bravo AF: 0.00830

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Batten-Turner congenital myopathy (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	-0.39
CADD	Benign	10
DANN	Benign	0.79
PhyloP100		0.81
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00089
dbscSNV1_RF	Benign	0.030
SpliceAI score (max)		0.040		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: rs113839156; hg19: chr7-143017753;