rs1553249924

Positions:

• chr1-201060735-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000069.3(CACNA1S):​c.3337T>C​(p.Tyr1113His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.28

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]

CACNA1S (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.3337T>C	p.Tyr1113His	missense_variant	26/44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.3337T>C	p.Tyr1113His	missense_variant	26/43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.3337T>C	p.Tyr1113His	missense_variant	26/44	1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 29, 2017

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CACNA1S-related disease. This sequence change replaces tyrosine with histidine at codon 1113 of the CACNA1S protein (p.Tyr1113His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.1	.;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Pathogenic	0.85
Sift	Benign	0.099	T;T
Sift4G	Benign	0.46	T;T
Polyphen		1.0	.;D
Vest4		0.88
MutPred		0.37		Loss of stability (P = 0.1173);Loss of stability (P = 0.1173);
MVP		0.95
MPC		0.59
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.48
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1553249924; hg19: chr1-201029863;