rs3764615

Positions:

• chr19-13453138-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001127222.2(CACNA1A):​c.400-123G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 909,456 control chromosomes in the GnomAD database, including 6,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1539 hom., cov: 32)
  • Exomes 𝑓: 0.097 (4699 hom.)
• Consequence: CACNA1A NM_001127222.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.115

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 19-13453138-C-A is Benign according to our data. Variant chr19-13453138-C-A is described in ClinVar as [Benign]. Clinvar id is 680137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.400-123G>T		intron_variant		ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.400-123G>T		intron_variant		1	NM_001127222.2	ENSP00000353362

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19175 AN: 151986 Hom.: 1535 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.0528

Gnomad EAS AF: 0.261

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0722

Gnomad OTH AF: 0.101

GnomAD4 exome AF: 0.0967 AC: 73233 AN: 757352 Hom.: 4699 AF XY: 0.0985 AC XY: 38456 AN XY: 390552

Gnomad4 AFR exome AF: 0.208

Gnomad4 AMR exome AF: 0.124

Gnomad4 ASJ exome AF: 0.0581

Gnomad4 EAS exome AF: 0.251

Gnomad4 SAS exome AF: 0.179

Gnomad4 FIN exome AF: 0.107

Gnomad4 NFE exome AF: 0.0719

Gnomad4 OTH exome AF: 0.101

GnomAD4 genome AF: 0.126 AC: 19205 AN: 152104 Hom.: 1539 Cov.: 32 AF XY: 0.130 AC XY: 9670 AN XY: 74366

Gnomad4 AFR AF: 0.207

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.0528

Gnomad4 EAS AF: 0.261

Gnomad4 SAS AF: 0.186

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.0722

Gnomad4 OTH AF: 0.101

Alfa AF: 0.0806 Hom.: 1266

Bravo AF: 0.127

Asia WGS AF: 0.211 AC: 732 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.8
DANN	Benign	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: rs3764615; hg19: chr19-13563952; COSMIC: COSV64192882;