19-13359752-C-T

Variant names:

• chr19-13359752-C-T
• rs1013100046
• NM_001127222.2:c.832G>A

Variant summary

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

The NM_001127222.2(CACNA1A):​c.832G>A​(p.Ala278Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,406,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 1.99

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a topological_domain Extracellular (size 86) in uniprot entity CAC1A_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_001127222.2
• PM2: Very rare variant in population databases, with high coverage
• 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: 3.9354 (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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.832G>A	p.Ala278Thr	missense_variant	Exon 6 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.832G>A	p.Ala278Thr	missense_variant	Exon 6 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.832G>A	p.Ala278Thr	missense_variant	Exon 6 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.832G>A	p.Ala278Thr	missense_variant	Exon 6 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.832G>A	p.Ala278Thr	missense_variant	Exon 6 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.832G>A	p.Ala278Thr	missense_variant	Exon 6 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.832G>A	p.Ala278Thr	missense_variant	Exon 6 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.691G>A	p.Ala231Thr	missense_variant	Exon 5 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.832G>A	p.Ala278Thr	missense_variant	Exon 6 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.832G>A	p.Ala278Thr	missense_variant	Exon 6 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.832G>A	p.Ala278Thr	missense_variant	Exon 6 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.832G>A	p.Ala278Thr	missense_variant	Exon 6 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.832G>A	p.Ala278Thr	missense_variant	Exon 6 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.832G>A	p.Ala278Thr	missense_variant	Exon 6 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.832G>A	p.Ala278Thr	missense_variant	Exon 6 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1406914 Hom.: 0 Cov.: 31 AF XY: 0.00000288 AC XY: 2 AN XY: 694564

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: 0.00

Gnomad4 NFE exome AF: 0.00000277

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Feb 16, 2022

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency 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 -

Developmental and epileptic encephalopathy, 42 Pathogenic:1

May 15, 2020

Breda Genetics srl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

We have detected a heterozygous variant in exon 6 of the CACNA1A gene, c.832G>A (p.Ala278Thr), rs1013100046, reference transcript NM_001127221.1. The variant is reported as uncertain for early infantile epileptic encephalopathy-42 and episodic ataxia type 2 in ClinVar (Variation ID: 570273). There is no information on frequency in gnomAD, 1000 Genomes or NHLI Exome Sequencing Project (ESP). The nucleotide position is conserved across 35 mammalian species (GERP RS: 5.27). In silico analysis indicates that the variant might be damaging. -

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

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 278 of the CACNA1A protein (p.Ala278Thr). 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: 570273). Invitae Evidence 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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.78	.;D;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.1	.;L;.;.;L;.;.;L;.;.;.;.;L;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.6	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.63
Sift	Benign	0.094	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.12	T;T;.;.;.;.;.;.;.;.;.;T;.;.;.
Polyphen		0.93	.;P;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.35
MutPred		0.47		Gain of glycosylation at A278 (P = 0.0021);Gain of glycosylation at A278 (P = 0.0021);Gain of glycosylation at A278 (P = 0.0021);Gain of glycosylation at A278 (P = 0.0021);Gain of glycosylation at A278 (P = 0.0021);.;Gain of glycosylation at A278 (P = 0.0021);Gain of glycosylation at A278 (P = 0.0021);Gain of glycosylation at A278 (P = 0.0021);Gain of glycosylation at A278 (P = 0.0021);Gain of glycosylation at A278 (P = 0.0021);Gain of glycosylation at A278 (P = 0.0021);Gain of glycosylation at A278 (P = 0.0021);Gain of glycosylation at A278 (P = 0.0021);Gain of glycosylation at A278 (P = 0.0021);
MVP		0.89
MPC		2.2
ClinPred		0.94	D
GERP RS		5.3
Varity_R		0.22
gMVP		0.80

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: rs1013100046; hg19: chr19-13470566; COSMIC: COSV64191328; COSMIC: COSV64191328;