rs1308599413

Positions:

• chr19-13317319-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001127222.2(CACNA1A):​c.1348T>C​(p.Ser450Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,445,378 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.44

Genes affected

CACNA1A (HGNC:1388): (calcium voltage-gated channel subunit alpha1 A) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016]

CACNA1A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity CAC1A_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1A. . Gene score misZ 5.7845 (greater than the threshold 3.09). Trascript score misZ 3.9354 (greater than threshold 3.09). GenCC has associacion of gene with benign paroxysmal torticollis of infancy, developmental and epileptic encephalopathy, 42, undetermined early-onset epileptic encephalopathy, episodic ataxia type 2, familial or sporadic hemiplegic migraine, spinocerebellar ataxia type 6, Lennox-Gastaut syndrome, migraine, familial hemiplegic, 1.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.1348T>C	p.Ser450Pro	missense_variant, splice_region_variant	11/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.1348T>C	p.Ser450Pro	missense_variant, splice_region_variant	11/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	11/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.1354T>C	p.Ser452Pro	missense_variant, splice_region_variant	11/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	11/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	11/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	11/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.1210T>C	p.Ser404Pro	missense_variant, splice_region_variant	10/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	11/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	11/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	11/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.1354T>C	p.Ser452Pro	missense_variant, splice_region_variant	11/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	11/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	11/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.1351T>C	p.Ser451Pro	missense_variant, splice_region_variant	11/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247570 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134310

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445378 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 715174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 9.10e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 31, 2016

- -

Vascular dementia Uncertain:1

Uncertain significance, no assertion criteria provided

research

Myllykangas group, University of Helsinki

Apr 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	2.9	.;.;.;.;M;.;.;M;.;.;.;.;M;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.65
Sift	Uncertain	0.024	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.060	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.56
MutPred		0.41		Loss of phosphorylation at S451 (P = 0.0508);.;Loss of phosphorylation at S451 (P = 0.0508);Loss of phosphorylation at S451 (P = 0.0508);Loss of phosphorylation at S451 (P = 0.0508);.;Loss of phosphorylation at S451 (P = 0.0508);Loss of phosphorylation at S451 (P = 0.0508);Loss of phosphorylation at S451 (P = 0.0508);Loss of phosphorylation at S451 (P = 0.0508);Loss of phosphorylation at S451 (P = 0.0508);.;Loss of phosphorylation at S451 (P = 0.0508);.;Loss of phosphorylation at S451 (P = 0.0508);
MVP		0.89
MPC		2.3
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.69
gMVP		0.90

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: rs1308599413; hg19: chr19-13428133;