rs147493705

chr7-143339519-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1 PM5 BP4_Strong BP6 BS2

The NM_000083.3(CLCN1):c.1480T>C(p.Phe494Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000242 in 1,612,644 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F494S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: CLCN1 NM_000083.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 8.01

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 Likely_benign. Variant got -5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000083.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-143339520-T-C is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.044286817).
• BP6: Variant 7-143339519-T-C is Benign according to our data. Variant chr7-143339519-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 418134.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCN1	NM_000083.3	c.1480T>C	p.Phe494Leu	missense_variant	14/23	ENST00000343257.7
CLCN1	NR_046453.2	n.1435T>C		non_coding_transcript_exon_variant	13/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCN1	ENST00000343257.7	c.1480T>C	p.Phe494Leu	missense_variant	14/23	1	NM_000083.3	P4
CLCN1	ENST00000432192.6	c.*765T>C		3_prime_UTR_variant, NMD_transcript_variant	14/23	1
CLCN1	ENST00000650516.2	c.1480T>C	p.Phe494Leu	missense_variant	14/23			A2

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 152170 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00417

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000342 AC: 86 AN: 251454 Hom.: 0 AF XY: 0.000287 AC XY: 39 AN XY: 135908

Gnomad AFR exome AF: 0.00406

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000136 AC: 198 AN: 1460356 Hom.: 0 Cov.: 31 AF XY: 0.000113 AC XY: 82 AN XY: 726588

Gnomad4 AFR exome AF: 0.00457

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000365

GnomAD4 genome AF: 0.00126 AC: 192 AN: 152288 Hom.: 2 Cov.: 32 AF XY: 0.00133 AC XY: 99 AN XY: 74464

Gnomad4 AFR AF: 0.00433

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000241 Hom.: 0

Bravo AF: 0.00141

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000354 AC: 43

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2018	A variant of uncertain significance has been identified in the CLCN1 gene. The F494L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The F494L variant is observed in 37/10402 (0.4%) alleles from individuals of African background, in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The F494L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, a missense variant at the same residue (F494S) and in nearby residues (A493E/V, R496S, G499R) have been reported in the Human Gene Mutation Database in association with CLCN1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 22, 2021	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	0.061
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.044	T
MetaSVM	Uncertain	-0.0019	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.49
Sift	Benign	0.13	T
Sift4G	Benign	0.10	T
Polyphen		0.052	B
Vest4		0.93
MutPred		0.49		Loss of catalytic residue at F494 (P = 0.0269);
MVP		0.94
MPC		0.40
ClinPred		0.10	T
GERP RS		5.1
Varity_R		0.71
gMVP		0.86

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: rs147493705; hg19: chr7-143036612;