rs28413664

chr19-13298605-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001127222.2(CACNA1A):c.3028C>G(p.Pro1010Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 1,538,708 control chromosomes in the GnomAD database, including 199 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (119 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (80 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.717

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CACNA1A
• BP4: Computational evidence support a benign effect (MetaRNN=0.0019551814).
• BP6: Variant 19-13298605-G-C is Benign according to our data. Variant chr19-13298605-G-C is described in ClinVar as [Benign]. Clinvar id is 128550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298605-G-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.3028C>G	p.Pro1010Ala	missense_variant	19/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3028C>G	p.Pro1010Ala	missense_variant	19/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 3276 AN: 152008 Hom.: 118 Cov.: 33

Gnomad AFR AF: 0.0732

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.00383 AC: 539 AN: 140816 Hom.: 17 AF XY: 0.00302 AC XY: 227 AN XY: 75194

Gnomad AFR exome AF: 0.0808

Gnomad AMR exome AF: 0.00350

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: 0.000268

Gnomad OTH exome AF: 0.00282

GnomAD4 exome AF: 0.00201 AC: 2789 AN: 1386584 Hom.: 80 Cov.: 32 AF XY: 0.00172 AC XY: 1178 AN XY: 683836

Gnomad4 AFR exome AF: 0.0735

Gnomad4 AMR exome AF: 0.00436

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000508

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000166

Gnomad4 OTH exome AF: 0.00481

GnomAD4 genome AF: 0.0216 AC: 3285 AN: 152124 Hom.: 119 Cov.: 33 AF XY: 0.0205 AC XY: 1528 AN XY: 74394

Gnomad4 AFR AF: 0.0732

Gnomad4 AMR AF: 0.0120

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.00605 Hom.: 9

Bravo AF: 0.0250

ESP6500AA AF: 0.0628 AC: 195

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00648 AC: 198

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 05, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	9.8
Dann	Benign	0.68
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.82	T;T;T;T;T;T;T;T;.;T;T;T;T;T;T
MetaRNN	Benign	0.0020	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.43	T
MutationTaster	Benign	0.97	N;N;N
PrimateAI	Pathogenic	0.79	T
Sift4G	Benign	0.58	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.17
MVP		0.71
MPC		1.1
ClinPred		0.0034	T
GERP RS		3.0
Varity_R		0.071
gMVP		0.28

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: rs28413664; hg19: chr19-13409419; COSMIC: COSV99081030;