7-143316197-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: -0.548

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 383610.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0703 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN1	NM_000083.3	c.-16C>G		5_prime_UTR_variant	1/23	ENST00000343257.7
CLCN1	NR_046453.2	n.87C>G		non_coding_transcript_exon_variant	1/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN1	ENST00000343257.7	c.-16C>G		5_prime_UTR_variant	1/23	1	NM_000083.3	P4
CLCN1	ENST00000650516.2	c.-16C>G		5_prime_UTR_variant	1/23			A2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 682 AN: 151748 Hom.: 11 Cov.: 32 FAILED QC

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

GnomAD3 exomes AF: 0.0117 AC: 2877 AN: 246616 Hom.: 118 AF XY: 0.00918 AC XY: 1228 AN XY: 133808

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 SAS exome AF: 0.000818

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

Gnomad4 AFR exome AF: 0.000569

Gnomad4 AMR exome AF: 0.0723

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.0151

Gnomad4 SAS exome AF: 0.000882

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000108

Gnomad4 OTH exome AF: 0.00246

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

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.0361

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00838

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00952

Alfa AF: 0.00411 Hom.: 2

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 31, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.41
Dann	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs191902231; hg19: chr7-143013290;