rs3764580

Positions:

• chr19-13285296-C-T

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.3554-90G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,463,610 control chromosomes in the GnomAD database, including 16,924 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1656 hom., cov: 31)
  • Exomes 𝑓: 0.14 (15268 hom.)
• Consequence: CACNA1A NM_001127222.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0120

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]

CACNA1A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-13285296-C-T is Benign according to our data. Variant chr19-13285296-C-T is described in ClinVar as [Benign]. Clinvar id is 1293083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3554-90G>A		intron_variant		ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3554-90G>A		intron_variant		1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.3566-90G>A		intron_variant		5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3560-90G>A		intron_variant		5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3557-90G>A		intron_variant		5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3557-90G>A		intron_variant		1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3557-90G>A		intron_variant		5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3416-90G>A		intron_variant		5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3557-90G>A		intron_variant		5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3566-90G>A		intron_variant		5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3557-90G>A		intron_variant		5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3560-90G>A		intron_variant		5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3557-90G>A		intron_variant		5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3557-90G>A		intron_variant		1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3557-90G>A		intron_variant		5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18594 AN: 152024 Hom.: 1655 Cov.: 31

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.141

GnomAD4 exome AF: 0.142 AC: 185599 AN: 1311468 Hom.: 15268 AF XY: 0.144 AC XY: 93563 AN XY: 651974

Gnomad4 AFR exome AF: 0.0248

Gnomad4 AMR exome AF: 0.276

Gnomad4 ASJ exome AF: 0.173

Gnomad4 EAS exome AF: 0.348

Gnomad4 SAS exome AF: 0.201

Gnomad4 FIN exome AF: 0.114

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.146

GnomAD4 genome AF: 0.122 AC: 18591 AN: 152142 Hom.: 1656 Cov.: 31 AF XY: 0.127 AC XY: 9456 AN XY: 74386

Gnomad4 AFR AF: 0.0281

Gnomad4 AMR AF: 0.217

Gnomad4 ASJ AF: 0.171

Gnomad4 EAS AF: 0.372

Gnomad4 SAS AF: 0.219

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.130

Gnomad4 OTH AF: 0.140

Alfa AF: 0.114 Hom.: 137

Bravo AF: 0.127

Asia WGS AF: 0.259 AC: 900 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 31, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 40% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 37. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.5
DANN	Benign	0.36

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: rs3764580; hg19: chr19-13396110; COSMIC: COSV64206127; COSMIC: COSV64206127;