19-13286794-C-A

Variant names:

• chr19-13286794-C-A
• rs371820430
• NM_001127222.2:c.3262G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS2

The NM_001127222.2(CACNA1A):​c.3262G>T​(p.Ala1088Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,660 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1088T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (1 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.915
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• episodic ataxia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• developmental and epileptic encephalopathy, 42

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• migraine, familial hemiplegic, 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• benign paroxysmal torticollis of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial or sporadic hemiplegic migraine

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05330047).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3262G>T	p.Ala1088Ser	missense_variant	Exon 20 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2	c.3265G>T	p.Ala1089Ser	missense_variant	Exon 20 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3262G>T	p.Ala1088Ser	missense_variant	Exon 20 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2	c.3265G>T	p.Ala1089Ser	missense_variant	Exon 20 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1	c.3274G>T	p.Ala1092Ser	missense_variant	Exon 20 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3268G>T	p.Ala1090Ser	missense_variant	Exon 20 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3265G>T	p.Ala1089Ser	missense_variant	Exon 20 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3265G>T	p.Ala1089Ser	missense_variant	Exon 20 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3265G>T	p.Ala1089Ser	missense_variant	Exon 20 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3124G>T	p.Ala1042Ser	missense_variant	Exon 19 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3265G>T	p.Ala1089Ser	missense_variant	Exon 20 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3274G>T	p.Ala1092Ser	missense_variant	Exon 20 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3265G>T	p.Ala1089Ser	missense_variant	Exon 20 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3268G>T	p.Ala1090Ser	missense_variant	Exon 20 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3265G>T	p.Ala1089Ser	missense_variant	Exon 20 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1	c.3265G>T	p.Ala1089Ser	missense_variant	Exon 20 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.3265G>T		non_coding_transcript_exon_variant	Exon 20 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.3262G>T		non_coding_transcript_exon_variant	Exon 20 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000822 AC: 2 AN: 243198 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460660 Hom.: 1 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726650

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111564

Other (OTH) AF: 0.00 AC: 0 AN: 60290

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000451 Hom.: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Dec 24, 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 serine, which is neutral and polar, at codon 1089 of the CACNA1A protein (p.Ala1089Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 1978185). 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) indicates that this missense variant is not expected to disrupt CACNA1A protein function with a negative predictive value of 95%. 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	Benign	0.070
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.0030
DANN	Benign	0.74
DEOGEN2	Benign	0.0	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.52	T;T;T;T;T;T;T;T;.;T;T;T;T;T;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.053	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.0	.;.;.;.;N;.;.;.;.;.;.;.;N;.;.
PhyloP100		-0.92
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.0	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.98	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.12
ClinPred		0.032	T
GERP RS		-10
Varity_R		0.028
gMVP		0.50
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs371820430; hg19: chr19-13397608;