rs200665694

chr1-201089415-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000069.3(CACNA1S):c.743C>T(p.Thr248Met) variant causes a missense change. The variant allele was found at a frequency of 0.000162 in 1,614,174 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T248T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 3.98

Genes affected

CACNA1S (HGNC:1397): (calcium voltage-gated channel subunit alpha1 S) This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2200591).
• BP6: Variant 1-201089415-G-A is Benign according to our data. Variant chr1-201089415-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 294774.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1S	NM_000069.3	c.743C>T	p.Thr248Met	missense_variant	6/44	ENST00000362061.4
CACNA1S	XM_005245478.4	c.743C>T	p.Thr248Met	missense_variant	6/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1S	ENST00000362061.4	c.743C>T	p.Thr248Met	missense_variant	6/44	1	NM_000069.3	P2

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000247 AC: 62 AN: 250752 Hom.: 0 AF XY: 0.000287 AC XY: 39 AN XY: 135698

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.000389

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000158 AC: 231 AN: 1461806 Hom.: 1 Cov.: 33 AF XY: 0.000171 AC XY: 124 AN XY: 727202

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000319

Gnomad4 NFE exome AF: 0.000169

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000203 AC: 31 AN: 152368 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74518

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000222 Hom.: 0

Bravo AF: 0.000136

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24195946) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 12, 2023	- -

Hypokalemic periodic paralysis, type 1 Uncertain:1 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 24, 2022	- -

Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 05, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D
Eigen	Benign	0.056
Eigen_PC	Benign	-0.035
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Pathogenic	0.86	D
MutationTaster	Benign	0.60	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.96	.;D
Vest4		0.28
MVP		0.94
MPC		0.14
ClinPred		0.31	T
GERP RS		3.9
Varity_R		0.11
gMVP		0.74

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: rs200665694; hg19: chr1-201058543; COSMIC: COSV100755440;