7-143321381-C-T

Variant names:

• chr7-143321381-C-T
• rs56307536
• NM_000083.3:c.450C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000083.3(CLCN1):​c.450C>T​(p.Tyr150Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,614,206 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (27 hom.)
• Consequence: CLCN1 NM_000083.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.167
• Publications: 0 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 7-143321381-C-T is Benign according to our data. Variant chr7-143321381-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 359099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.167 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00875 (1333/152330) while in subpopulation AFR AF = 0.0302 (1257/41560). AF 95% confidence interval is 0.0289. There are 10 homozygotes in GnomAd4. There are 636 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.450C>T	p.Tyr150Tyr	synonymous	Exon 4 of 23	NP_000074.3
	CLCN1	NR_046453.2		n.552C>T		non_coding_transcript_exon	Exon 4 of 22

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.450C>T	p.Tyr150Tyr	synonymous	Exon 4 of 23	ENSP00000339867.2
	CLCN1	ENST00000432192.6	TSL:1	n.216C>T		non_coding_transcript_exon	Exon 3 of 23	ENSP00000395949.2
	CLCN1	ENST00000650516.2		c.450C>T	p.Tyr150Tyr	synonymous	Exon 4 of 23	ENSP00000498052.2

Frequencies

GnomAD3 genomes AF: 0.00870 AC: 1324 AN: 152212 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00258 AC: 648 AN: 251386 AF XY: 0.00194

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00102 AC: 1496 AN: 1461876 Hom.: 27 Cov.: 33 AF XY: 0.000891 AC XY: 648 AN XY: 727246

African (AFR) AF: 0.0332 AC: 1112 AN: 33480

American (AMR) AF: 0.00195 AC: 87 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000336 AC: 29 AN: 86258

European-Finnish (FIN) AF: 0.000524 AC: 28 AN: 53412

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.0000908 AC: 101 AN: 1112006

Other (OTH) AF: 0.00220 AC: 133 AN: 60396

GnomAD4 genome AF: 0.00875 AC: 1333 AN: 152330 Hom.: 10 Cov.: 33 AF XY: 0.00854 AC XY: 636 AN XY: 74482

African (AFR) AF: 0.0302 AC: 1257 AN: 41560

American (AMR) AF: 0.00359 AC: 55 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68032

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00406 Hom.: 6

Bravo AF: 0.0102

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form (2)
-	-	2	not specified (2)
-	-	1	Batten-Turner congenital myopathy (1)
-	-	1	CLCN1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.55
DANN	Benign	0.41
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs56307536; hg19: chr7-143018474;