rs1013100046

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr19-13359752-C-A
• chr19-13359752-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_001127222.2(CACNA1A):​c.832G>T​(p.Ala278Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000128 in 1,559,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 4 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33664244).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.832G>T	p.Ala278Ser	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>T	p.Ala278Ser	missense_variant	Exon 6 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.832G>T	p.Ala278Ser	missense_variant	Exon 6 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.832G>T	p.Ala278Ser	missense_variant	Exon 6 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.832G>T	p.Ala278Ser	missense_variant	Exon 6 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.832G>T	p.Ala278Ser	missense_variant	Exon 6 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.832G>T	p.Ala278Ser	missense_variant	Exon 6 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.691G>T	p.Ala231Ser	missense_variant	Exon 5 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.832G>T	p.Ala278Ser	missense_variant	Exon 6 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.832G>T	p.Ala278Ser	missense_variant	Exon 6 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.832G>T	p.Ala278Ser	missense_variant	Exon 6 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.832G>T	p.Ala278Ser	missense_variant	Exon 6 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.832G>T	p.Ala278Ser	missense_variant	Exon 6 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.832G>T	p.Ala278Ser	missense_variant	Exon 6 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.832G>T	p.Ala278Ser	missense_variant	Exon 6 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.11e-7 AC: 1 AN: 1406914 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 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: 9.23e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74334

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Sep 14, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in an individual undergoing genetic testing for clinical suspicion of CADASIL, but additional clinical information was not included (Maksemous et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27881154) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Uncertain	0.69	.;D;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	0.13	.;N;.;.;N;.;.;N;.;.;.;.;N;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.4	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.42
Sift	Benign	0.23	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.30	T;T;.;.;.;.;.;.;.;.;.;T;.;.;.
Polyphen		0.062	.;B;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.092
MutPred		0.47		Gain of glycosylation at A278 (P = 0.0047);Gain of glycosylation at A278 (P = 0.0047);Gain of glycosylation at A278 (P = 0.0047);Gain of glycosylation at A278 (P = 0.0047);Gain of glycosylation at A278 (P = 0.0047);.;Gain of glycosylation at A278 (P = 0.0047);Gain of glycosylation at A278 (P = 0.0047);Gain of glycosylation at A278 (P = 0.0047);Gain of glycosylation at A278 (P = 0.0047);Gain of glycosylation at A278 (P = 0.0047);Gain of glycosylation at A278 (P = 0.0047);Gain of glycosylation at A278 (P = 0.0047);Gain of glycosylation at A278 (P = 0.0047);Gain of glycosylation at A278 (P = 0.0047);
MVP		0.86
MPC		2.1
ClinPred		0.82	D
GERP RS		5.3
Varity_R		0.16
gMVP		0.76

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;