rs16043

Positions:

• chr19-13214614-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001127222.2(CACNA1A):​c.5732-6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,610,218 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00087 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (24 hom.)
• Consequence: CACNA1A NM_001127222.2 splice_region, intron
• Scores: Splicing: ADA: 0.00003880
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0360

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=-0.81).
• BP6: Variant 19-13214614-A-G is Benign according to our data. Variant chr19-13214614-A-G is described in ClinVar as [Benign]. Clinvar id is 285526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13214614-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000867 (132/152302) while in subpopulation SAS AF= 0.0153 (74/4828). AF 95% confidence interval is 0.0125. There are 2 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 132 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5732-6T>C		splice_region_variant, intron_variant		ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5732-6T>C		splice_region_variant, intron_variant		1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5750-6T>C		splice_region_variant, intron_variant		5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5738-6T>C		splice_region_variant, intron_variant		5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.5735-6T>C		splice_region_variant, intron_variant		5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.5735-6T>C		splice_region_variant, intron_variant		1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.5735-6T>C		splice_region_variant, intron_variant		5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5594-6T>C		splice_region_variant, intron_variant		5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5735-6T>C		splice_region_variant, intron_variant		5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.5750-6T>C		splice_region_variant, intron_variant		5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5741-6T>C		splice_region_variant, intron_variant		5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5738-6T>C		splice_region_variant, intron_variant		5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.5735-6T>C		splice_region_variant, intron_variant		5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.5735-6T>C		splice_region_variant, intron_variant		1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.5735-6T>C		splice_region_variant, intron_variant		5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*34-6T>C		splice_region_variant, intron_variant		5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152184 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00236 AC: 580 AN: 245390 Hom.: 13 AF XY: 0.00312 AC XY: 415 AN XY: 133178

Gnomad AFR exome AF: 0.000732

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.0176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000261

Gnomad OTH exome AF: 0.000501

GnomAD4 exome AF: 0.00116 AC: 1695 AN: 1457916 Hom.: 24 Cov.: 30 AF XY: 0.00163 AC XY: 1181 AN XY: 725176

Gnomad4 AFR exome AF: 0.000539

Gnomad4 AMR exome AF: 0.0000899

Gnomad4 ASJ exome AF: 0.000269

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0156

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000241

Gnomad4 OTH exome AF: 0.000996

GnomAD4 genome AF: 0.000867 AC: 132 AN: 152302 Hom.: 2 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74474

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0153

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000336 Hom.: 0

Bravo AF: 0.000525

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 27, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 05, 2024	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

CACNA1A-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.68
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000039
dbscSNV1_RF	Benign	0.026
SpliceAI score (max)		0.010		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: rs16043; hg19: chr19-13325428;