rs78085922

Positions:

• chr7-143346211-G-A
• chr7-143346211-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000083.3(CLCN1):​c.2244G>A​(p.Leu748=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,613,444 control chromosomes in the GnomAD database, including 218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L748L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (43 hom., cov: 31)
  • Exomes 𝑓: 0.013 (175 hom.)
• Consequence: CLCN1 NM_000083.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.89

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 7-143346211-G-A is Benign according to our data. Variant chr7-143346211-G-A is described in ClinVar as [Benign]. Clinvar id is 359122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-143346211-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0171 (2608/152086) while in subpopulation AFR AF= 0.0306 (1269/41460). AF 95% confidence interval is 0.0292. There are 43 homozygotes in gnomad4. There are 1215 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 43 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN1	NM_000083.3	c.2244G>A	p.Leu748=	synonymous_variant	18/23	ENST00000343257.7
CLCN1	NR_046453.2	n.2199G>A		non_coding_transcript_exon_variant	17/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN1	ENST00000343257.7	c.2244G>A	p.Leu748=	synonymous_variant	18/23	1	NM_000083.3	P4
CLCN1	ENST00000432192.6	c.*1529G>A		3_prime_UTR_variant, NMD_transcript_variant	18/23	1
CLCN1	ENST00000650516.2	c.2244G>A	p.Leu748=	synonymous_variant	18/23			A2

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2607 AN: 151968 Hom.: 43 Cov.: 31

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0134

Gnomad ASJ AF: 0.0554

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.00444

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0130 AC: 3258 AN: 251308 Hom.: 33 AF XY: 0.0127 AC XY: 1722 AN XY: 135852

Gnomad AFR exome AF: 0.0308

Gnomad AMR exome AF: 0.00888

Gnomad ASJ exome AF: 0.0524

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00640

Gnomad FIN exome AF: 0.00463

Gnomad NFE exome AF: 0.0133

Gnomad OTH exome AF: 0.0191

GnomAD4 exome AF: 0.0131 AC: 19081 AN: 1461358 Hom.: 175 Cov.: 33 AF XY: 0.0128 AC XY: 9338 AN XY: 727014

Gnomad4 AFR exome AF: 0.0325

Gnomad4 AMR exome AF: 0.00993

Gnomad4 ASJ exome AF: 0.0500

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00678

Gnomad4 FIN exome AF: 0.00465

Gnomad4 NFE exome AF: 0.0129

Gnomad4 OTH exome AF: 0.0159

GnomAD4 genome AF: 0.0171 AC: 2608 AN: 152086 Hom.: 43 Cov.: 31 AF XY: 0.0163 AC XY: 1215 AN XY: 74348

Gnomad4 AFR AF: 0.0306

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.0554

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00601

Gnomad4 FIN AF: 0.00444

Gnomad4 NFE AF: 0.0120

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0143 Hom.: 14

Bravo AF: 0.0197

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0151

EpiControl AF: 0.0162

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 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. -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Batten-Turner congenital myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Congenital myotonia, autosomal recessive form;C2936781:Congenital myotonia, autosomal dominant form Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	6.1
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs78085922; hg19: chr7-143043304;