7-143342363-C-T

Variant names:

• chr7-143342363-C-T
• rs41276057
• NM_000083.3:c.1797-9C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000083.3(CLCN1):​c.1797-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 1,613,954 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (12 hom., cov: 32)
  • Exomes 𝑓: 0.012 (151 hom.)
• Consequence: CLCN1 NM_000083.3 intron
• Scores: Splicing: ADA: 0.5071
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.232
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 7-143342363-C-T is Benign according to our data. Variant chr7-143342363-C-T is described in ClinVar as Benign. ClinVar VariationId is 359113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 12 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.1797-9C>T		intron	N/A	NP_000074.3
	CLCN1	NR_046453.2		n.1752-9C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCN1	ENST00000343257.7	TSL:1 MANE Select	c.1797-9C>T		intron	N/A	ENSP00000339867.2
	CLCN1	ENST00000432192.6	TSL:1	n.*1082-9C>T		intron	N/A	ENSP00000395949.2
	CLCN1	ENST00000650516.2		c.1797-9C>T		intron	N/A	ENSP00000498052.2

Frequencies

GnomAD3 genomes AF: 0.00918 AC: 1396 AN: 152122 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.0553

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0109 AC: 2733 AN: 251332 AF XY: 0.0111

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00740

Gnomad ASJ exome AF: 0.0525

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00462

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.0179

GnomAD4 exome AF: 0.0123 AC: 17952 AN: 1461714 Hom.: 151 Cov.: 32 AF XY: 0.0122 AC XY: 8865 AN XY: 727168

African (AFR) AF: 0.00215 AC: 72 AN: 33480

American (AMR) AF: 0.00834 AC: 373 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0502 AC: 1311 AN: 26134

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

South Asian (SAS) AF: 0.00673 AC: 580 AN: 86226

European-Finnish (FIN) AF: 0.00466 AC: 249 AN: 53414

Middle Eastern (MID) AF: 0.00988 AC: 57 AN: 5768

European-Non Finnish (NFE) AF: 0.0130 AC: 14474 AN: 1111880

Other (OTH) AF: 0.0138 AC: 836 AN: 60392

GnomAD4 genome AF: 0.00916 AC: 1395 AN: 152240 Hom.: 12 Cov.: 32 AF XY: 0.00869 AC XY: 647 AN XY: 74452

African (AFR) AF: 0.00272 AC: 113 AN: 41546

American (AMR) AF: 0.0111 AC: 169 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0553 AC: 192 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4820

European-Finnish (FIN) AF: 0.00443 AC: 47 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0119 AC: 811 AN: 68004

Other (OTH) AF: 0.0118 AC: 25 AN: 2110

Alfa AF: 0.0135 Hom.: 18

Bravo AF: 0.00993

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0150

EpiControl AF: 0.0162

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Benign	0.72
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.51
dbscSNV1_RF	Benign	0.49
SpliceAI score (max)		0.030		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: rs41276057; hg19: chr7-143039456;