rs757840865

Positions:

• chr1-201062077-C-A
• chr1-201062077-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000362061.4(CACNA1S):​c.2920G>T​(p.Val974Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V974M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CACNA1S ENST00000362061.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.361

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1497902).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3	c.2920G>T	p.Val974Leu	missense_variant	24/44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4	c.2920G>T	p.Val974Leu	missense_variant	24/43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4	c.2920G>T	p.Val974Leu	missense_variant	24/44	1	NM_000069.3	ENSP00000355192	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461580 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727052

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.32	T;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.7	.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.42	N;N
REVEL	Benign	0.14
Sift	Benign	0.38	T;T
Sift4G	Benign	0.60	T;T
Polyphen		0.032	.;B
Vest4		0.12
MutPred		0.29		Loss of methylation at K976 (P = 0.0677);Loss of methylation at K976 (P = 0.0677);
MVP		0.79
MPC		0.11
ClinPred		0.11	T
GERP RS		3.0
Varity_R		0.038
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs757840865; hg19: chr1-201031205;