rs201230929

Positions:

• chr19-13283267-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001127222.2(CACNA1A):​c.3822C>T​(p.Asn1274Asn) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000471 in 1,613,638 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.0006111
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -2.11

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 19-13283267-G-A is Benign according to our data. Variant chr19-13283267-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 384147.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
• BP7: Synonymous conserved (PhyloP=-2.11 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00019 (29/152236) while in subpopulation AFR AF= 0.000699 (29/41460). AF 95% confidence interval is 0.000499. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3822C>T	p.Asn1274Asn	splice_region_variant, synonymous_variant	22/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3822C>T	p.Asn1274Asn	splice_region_variant, synonymous_variant	22/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.3834C>T	p.Asn1278Asn	splice_region_variant, synonymous_variant	22/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3828C>T	p.Asn1276Asn	splice_region_variant, synonymous_variant	22/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3825C>T	p.Asn1275Asn	splice_region_variant, synonymous_variant	22/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3825C>T	p.Asn1275Asn	splice_region_variant, synonymous_variant	22/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3825C>T	p.Asn1275Asn	splice_region_variant, synonymous_variant	22/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3684C>T	p.Asn1228Asn	splice_region_variant, synonymous_variant	21/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3825C>T	p.Asn1275Asn	splice_region_variant, synonymous_variant	22/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3834C>T	p.Asn1278Asn	splice_region_variant, synonymous_variant	22/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3825C>T	p.Asn1275Asn	splice_region_variant, synonymous_variant	22/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3828C>T	p.Asn1276Asn	splice_region_variant, synonymous_variant	22/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3825C>T	p.Asn1275Asn	splice_region_variant, synonymous_variant	22/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3825C>T	p.Asn1275Asn	splice_region_variant, synonymous_variant	22/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3825C>T	p.Asn1275Asn	splice_region_variant, synonymous_variant	22/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.000190 AC: 29 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000699

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000563 AC: 14 AN: 248766 Hom.: 0 AF XY: 0.0000519 AC XY: 7 AN XY: 134890

Gnomad AFR exome AF: 0.000579

Gnomad AMR exome AF: 0.00

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: 0.0000444

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000322 AC: 47 AN: 1461402 Hom.: 0 Cov.: 30 AF XY: 0.0000289 AC XY: 21 AN XY: 726954

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74378

Gnomad4 AFR AF: 0.000699

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000123 Hom.: 1

Bravo AF: 0.000230

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 13, 2018	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

This sequence change affects codon 1275 of the CACNA1A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CACNA1A protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs201230929, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. 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: 384147). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	2.9
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00061
dbscSNV1_RF	Benign	0.082
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: rs201230929; hg19: chr19-13394081;