19-13312749-T-C

Variant names:

• chr19-13312749-T-C
• rs374764234
• NM_001127222.2:c.1588A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1 PP2 BP4 BS2

The NM_001127222.2(CACNA1A):​c.1588A>G​(p.Met530Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000568 in 1,585,246 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: 0.0000056 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.80

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 -2 ACMG points.

• PM1: In a repeat II (size 244) in uniprot entity CAC1A_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_001127222.2
• 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=0.37116665).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.1588A>G	p.Met530Val	missense_variant	Exon 12 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.1588A>G	p.Met530Val	missense_variant	Exon 12 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.1591A>G	p.Met531Val	missense_variant	Exon 12 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.1594A>G	p.Met532Val	missense_variant	Exon 12 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.1591A>G	p.Met531Val	missense_variant	Exon 12 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.1591A>G	p.Met531Val	missense_variant	Exon 12 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.1591A>G	p.Met531Val	missense_variant	Exon 12 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.1450A>G	p.Met484Val	missense_variant	Exon 11 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.1591A>G	p.Met531Val	missense_variant	Exon 12 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.1591A>G	p.Met531Val	missense_variant	Exon 12 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.1591A>G	p.Met531Val	missense_variant	Exon 12 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.1594A>G	p.Met532Val	missense_variant	Exon 12 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.1591A>G	p.Met531Val	missense_variant	Exon 12 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.1591A>G	p.Met531Val	missense_variant	Exon 12 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.1591A>G	p.Met531Val	missense_variant	Exon 12 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000444 AC: 1 AN: 225256 Hom.: 0 AF XY: 0.00000812 AC XY: 1 AN XY: 123142

Gnomad AFR exome AF: 0.0000744

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

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: 0.00000558 AC: 8 AN: 1433064 Hom.: 0 Cov.: 28 AF XY: 0.00000421 AC XY: 3 AN XY: 712662

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: 0.00000728

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74386

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000828 AC: 1

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

Jun 09, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CACNA1A-related disease. This variant is present in population databases (rs374764234, ExAC 0.01%). This sequence change replaces methionine with valine at codon 531 of the CACNA1A protein (p.Met531Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. -

not provided Uncertain:1

Aug 23, 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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.26
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Benign	0.027	.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.032
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	0.31	.;.;.;.;N;.;.;N;.;.;.;.;N;.;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.74
Sift	Benign	0.078	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.051	T;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.61
MutPred		0.58		Gain of catalytic residue at M531 (P = 0.0663);.;Gain of catalytic residue at M531 (P = 0.0663);Gain of catalytic residue at M531 (P = 0.0663);Gain of catalytic residue at M531 (P = 0.0663);.;Gain of catalytic residue at M531 (P = 0.0663);Gain of catalytic residue at M531 (P = 0.0663);Gain of catalytic residue at M531 (P = 0.0663);Gain of catalytic residue at M531 (P = 0.0663);Gain of catalytic residue at M531 (P = 0.0663);.;Gain of catalytic residue at M531 (P = 0.0663);.;Gain of catalytic residue at M531 (P = 0.0663);
MVP		0.99
MPC		1.3
ClinPred		0.22	T
GERP RS		4.1
Varity_R		0.30
gMVP		0.77

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: rs374764234; hg19: chr19-13423563;