rs191902231

Variant names:

• chr7-143316197-C-G
• rs191902231
• NM_000083.3:c.-16C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-143316197-C-G
• chr7-143316197-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000083.3(CLCN1):​c.-16C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,455,416 control chromosomes in the GnomAD database, including 150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (150 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: -0.548
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-143316197-C-G is Benign according to our data. Variant chr7-143316197-C-G is described in ClinVar as Benign. ClinVar VariationId is 383610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0703 is higher than 0.05.

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.-16C>G		5_prime_UTR	Exon 1 of 23	NP_000074.3	P35523
	CLCN1	NR_046453.2		n.87C>G		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.-16C>G		5_prime_UTR	Exon 1 of 23	ENSP00000339867.2	P35523
	CLCN1	ENST00000650516.2		c.-16C>G		5_prime_UTR	Exon 1 of 23	ENSP00000498052.2	A0A3B3IU72
	CLCN1	ENST00000958857.1		c.-16C>G		upstream_gene	N/A	ENSP00000628916.1

Frequencies

GnomAD3 genomes AF: 0.00449 AC: 682 AN: 151748 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0362

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00836

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00962

GnomAD2 exomes AF: 0.0117 AC: 2877 AN: 246616 AF XY: 0.00918

Gnomad AFR exome AF: 0.000881

Gnomad AMR exome AF: 0.0761

Gnomad ASJ exome AF: 0.000700

Gnomad EAS exome AF: 0.00699

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00290 AC: 4216 AN: 1455416 Hom.: 150 Cov.: 31 AF XY: 0.00261 AC XY: 1887 AN XY: 724196

African (AFR) AF: 0.000569 AC: 19 AN: 33408

American (AMR) AF: 0.0723 AC: 3233 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26118

East Asian (EAS) AF: 0.0151 AC: 600 AN: 39668

South Asian (SAS) AF: 0.000882 AC: 76 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51180

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5760

European-Non Finnish (NFE) AF: 0.000108 AC: 120 AN: 1108188

Other (OTH) AF: 0.00246 AC: 148 AN: 60220

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00448 AC: 681 AN: 151864 Hom.: 11 Cov.: 32 AF XY: 0.00477 AC XY: 354 AN XY: 74226

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

African (AFR) AF: 0.00123 AC: 51 AN: 41418

American (AMR) AF: 0.0361 AC: 548 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00838 AC: 43 AN: 5132

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

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

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67972

Other (OTH) AF: 0.00952 AC: 20 AN: 2100

⚠️ 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: 0.00411 Hom.: 2

ClinVar

ClinVar submissions

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	-0.83
CADD	Benign	0.41
DANN	Benign	0.69
PhyloP100		-0.55
PromoterAI		-0.13	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: rs191902231; hg19: chr7-143013290;