rs1001063428

Variant names:

• chr19-13228737-C-T
• rs1001063428
• ENST00000573710.7:c.5593G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2 PP3_Moderate BS2

The NM_001127221.2(CACNA1A):​c.5590G>A​(p.Gly1864Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000483 in 1,449,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CACNA1A NM_001127221.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.80

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant in the CACNA1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. Gene score misZ: 5.7845 (above the threshold of 3.09). Trascript score misZ: 5.4429 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5529-1210G>A		intron_variant	Intron 36 of 46	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000573710.7	c.5593G>A	p.Gly1865Ser	missense_variant	Exon 37 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000637769.1	c.5590G>A	p.Gly1864Ser	missense_variant	Exon 37 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000637736.1	c.5449G>A	p.Gly1817Ser	missense_variant	Exon 36 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5590G>A	p.Gly1864Ser	missense_variant	Exon 37 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637927.1	c.5593G>A	p.Gly1865Ser	missense_variant	Exon 37 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000638009.2	c.5590G>A	p.Gly1864Ser	missense_variant	Exon 37 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000360228.11	c.5529-1210G>A		intron_variant	Intron 36 of 46	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5547-1210G>A		intron_variant	Intron 37 of 47	5		ENSP00000489829.1
CACNA1A	ENST00000635727.1	c.5532-1210G>A		intron_variant	Intron 36 of 46	5		ENSP00000490001.1
CACNA1A	ENST00000636012.1	c.5532-1210G>A		intron_variant	Intron 36 of 45	5		ENSP00000490223.1
CACNA1A	ENST00000637432.1	c.5547-1210G>A		intron_variant	Intron 37 of 47	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5538-1210G>A		intron_variant	Intron 37 of 47	5		ENSP00000490578.1
CACNA1A	ENST00000635895.1	c.5532-1210G>A		intron_variant	Intron 36 of 46	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1	c.5532-1210G>A		intron_variant	Intron 36 of 45	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.155+1345G>A		intron_variant	Intron 2 of 9	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000483 AC: 7 AN: 1449458 Hom.: 0 Cov.: 28 AF XY: 0.00000277 AC XY: 2 AN XY: 720882

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: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000542

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1

Apr 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1864 of the CACNA1A protein (p.Gly1864Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 571669). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNA1A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Nov 17, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;.;.;.;.;T;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.45	D
Sift4G	Pathogenic	0.0	.;.;D;.;.;.;.;.
MutPred		0.27		Gain of phosphorylation at G1864 (P = 0.0778);Gain of phosphorylation at G1864 (P = 0.0778);.;.;Gain of phosphorylation at G1864 (P = 0.0778);.;.;.;
MVP		0.95
ClinPred		0.83	D
GERP RS		4.0

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: rs1001063428; hg19: chr19-13339551;