19-13208877-G-T

Variant names:

• chr19-13208877-G-T
• rs16052
• NM_001127222.2:c.6659C>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001127222.2(CACNA1A):​c.6659C>A​(p.Pro2220His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000473 in 1,459,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.81

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 -5 ACMG points.

• 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=0.23570347).
• BS2: High AC in GnomAdExome4 at 65 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6659C>A	p.Pro2220His	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.6659C>A	p.Pro2220His	missense_variant	Exon 46 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6677C>A	p.Pro2226His	missense_variant	Exon 47 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6665C>A	p.Pro2222His	missense_variant	Exon 46 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6662C>A	p.Pro2221His	missense_variant	Exon 46 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6662C>A	p.Pro2221His	missense_variant	Exon 46 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6626C>A	p.Pro2209His	missense_variant	Exon 45 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6521C>A	p.Pro2174His	missense_variant	Exon 45 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6662C>A	p.Pro2221His	missense_variant	Exon 46 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6677C>A	p.Pro2226His	missense_variant	Exon 47 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6668C>A	p.Pro2223His	missense_variant	Exon 47 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6665C>A	p.Pro2222His	missense_variant	Exon 46 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6662C>A	p.Pro2221His	missense_variant	Exon 46 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6662C>A	p.Pro2221His	missense_variant	Exon 46 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6626C>A	p.Pro2209His	missense_variant	Exon 45 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*925C>A		downstream_gene_variant		5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.0000266 AC: 4 AN: 150462 Hom.: 0 Cov.: 31

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: 0.0000592

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000496 AC: 65 AN: 1309458 Hom.: 0 Cov.: 76 AF XY: 0.0000464 AC XY: 30 AN XY: 646842

Gnomad4 AFR exome AF: 0.0000345

Gnomad4 AMR exome AF: 0.0000590

Gnomad4 ASJ exome AF: 0.0000416

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000621

Gnomad4 NFE exome AF: 0.0000568

Gnomad4 OTH exome AF: 0.0000183

GnomAD4 genome AF: 0.0000266 AC: 4 AN: 150462 Hom.: 0 Cov.: 31 AF XY: 0.0000136 AC XY: 1 AN XY: 73422

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: 0.0000592

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Episodic ataxia type 2 Uncertain:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 2221 of the CACNA1A protein (p.Pro2221His). 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: 432563). 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. -

Inborn genetic diseases Uncertain:1

Jan 19, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P2221H variant (also known as c.6662C>A), located in coding exon 46 of the CACNA1A gene, results from a C to A substitution at nucleotide position 6662. The proline at codon 2221 is replaced by histidine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Jan 20, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15979945) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.0025	.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.78	T;T;T;T;T;T;T;T;T;T;.;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.55	.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.71	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.26
Sift	Benign	0.13	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.16	T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.20
MutPred		0.28		.;.;Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);.;.;Loss of relative solvent accessibility (P = 0.0186);.;.;.;.;Loss of relative solvent accessibility (P = 0.0186);.;.;.;.;.;
MVP		0.71
MPC		0.98
ClinPred		0.48	T
GERP RS		2.7
Varity_R		0.087
gMVP		0.17

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: rs16052; hg19: chr19-13319691;