rs374063403

chr19-13212668-C-Achr19-13212668-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001127222.2(CACNA1A):c.6013G>T(p.Ala2005Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000735 in 1,360,538 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. A2005T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.06

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CACNA1A
• BP4: Computational evidence support a benign effect (MetaRNN=0.17545012).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.6013G>T	p.Ala2005Ser	missense_variant	41/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6013G>T	p.Ala2005Ser	missense_variant	41/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000125 AC: 2 AN: 159378 Hom.: 0 AF XY: 0.0000119 AC XY: 1 AN XY: 84006

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000491

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000686

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.35e-7 AC: 1 AN: 1360538 Hom.: 0 Cov.: 33 AF XY: 0.00000150 AC XY: 1 AN XY: 665500

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000846 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	23
Dann	Benign	0.91
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.16	D
MutationTaster	Benign	0.83	D;D;D
PrimateAI	Uncertain	0.55	T
Sift4G	Benign	0.59	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.11
MutPred		0.25		.;.;Gain of phosphorylation at A2006 (P = 0.0359);Gain of phosphorylation at A2006 (P = 0.0359);Gain of phosphorylation at A2006 (P = 0.0359);.;.;Gain of phosphorylation at A2006 (P = 0.0359);.;.;.;Gain of phosphorylation at A2006 (P = 0.0359);Gain of phosphorylation at A2006 (P = 0.0359);.;Gain of phosphorylation at A2006 (P = 0.0359);.;.;.;
MVP		0.82
MPC		0.67
ClinPred		0.35	T
GERP RS		2.4
Varity_R		0.065
gMVP		0.19

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: rs374063403; hg19: chr19-13323482;