19-13208830-C-A

Variant names:

• chr19-13208830-C-A
• rs752808137
• NM_001127222.2:c.6706G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001127222.2(CACNA1A):​c.6706G>T​(p.Gly2236Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000746 in 1,339,714 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2236S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.908

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 2 ACMG points.

• 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=0.36458227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6706G>T	p.Gly2236Cys	missense_variant	Exon 46 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6706G>T	p.Gly2236Cys	missense_variant	Exon 46 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6724G>T	p.Gly2242Cys	missense_variant	Exon 47 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6712G>T	p.Gly2238Cys	missense_variant	Exon 46 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6709G>T	p.Gly2237Cys	missense_variant	Exon 46 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6709G>T	p.Gly2237Cys	missense_variant	Exon 46 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6673G>T	p.Gly2225Cys	missense_variant	Exon 45 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6568G>T	p.Gly2190Cys	missense_variant	Exon 45 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6709G>T	p.Gly2237Cys	missense_variant	Exon 46 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6724G>T	p.Gly2242Cys	missense_variant	Exon 47 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6715G>T	p.Gly2239Cys	missense_variant	Exon 47 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6712G>T	p.Gly2238Cys	missense_variant	Exon 46 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6709G>T	p.Gly2237Cys	missense_variant	Exon 46 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6709G>T	p.Gly2237Cys	missense_variant	Exon 46 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6673G>T	p.Gly2225Cys	missense_variant	Exon 45 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*972G>T		downstream_gene_variant		5		ENSP00000490190.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.46e-7 AC: 1 AN: 1339714 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 661154

Gnomad4 AFR exome AF: 0.0000330

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Apr 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 2237 of the CACNA1A protein (p.Gly2237Cys). 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: 476274). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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	0.10
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.81	T;T;T;D;D;T;T;D;T;D;.;T;T;T;D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.3	.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-2.1	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.31
Sift	Benign	0.25	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.15	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.21
MutPred		0.25		.;.;Loss of methylation at R2238 (P = 0.0722);Loss of methylation at R2238 (P = 0.0722);Loss of methylation at R2238 (P = 0.0722);.;.;Loss of methylation at R2238 (P = 0.0722);.;.;.;.;Loss of methylation at R2238 (P = 0.0722);.;.;.;.;.;
MVP		0.91
MPC		0.97
ClinPred		0.72	D
GERP RS		0.045
Varity_R		0.17
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: rs752808137; hg19: chr19-13319644;