rs908321451

Variant names:

• chr19-13303783-C-T
• rs908321451
• NM_001127222.2:c.2088G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001127222.2(CACNA1A):​c.2088G>A​(p.Leu696Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.594

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2088G>A	p.Leu696Leu	synonymous_variant	Exon 16 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2088G>A	p.Leu696Leu	synonymous_variant	Exon 16 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2091G>A	p.Leu697Leu	synonymous_variant	Exon 16 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2094G>A	p.Leu698Leu	synonymous_variant	Exon 16 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2091G>A	p.Leu697Leu	synonymous_variant	Exon 16 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2091G>A	p.Leu697Leu	synonymous_variant	Exon 16 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2091G>A	p.Leu697Leu	synonymous_variant	Exon 16 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.1950G>A	p.Leu650Leu	synonymous_variant	Exon 15 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2091G>A	p.Leu697Leu	synonymous_variant	Exon 16 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2091G>A	p.Leu697Leu	synonymous_variant	Exon 16 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2091G>A	p.Leu697Leu	synonymous_variant	Exon 16 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2094G>A	p.Leu698Leu	synonymous_variant	Exon 16 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2091G>A	p.Leu697Leu	synonymous_variant	Exon 16 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2091G>A	p.Leu697Leu	synonymous_variant	Exon 16 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2091G>A	p.Leu697Leu	synonymous_variant	Exon 16 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459464 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726212

Gnomad4 AFR exome AF: 0.00

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Aug 17, 2016

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 446906). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. This sequence change affects codon 697 of the CACNA1A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CACNA1A protein. -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1A NM_001127222.1 exon 16 p.Leu696= (c.2088G>A): This variant has not been reported in the literature and is not present in large control databases. This variant is present in ClinVar (Variation ID:446906). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant is a silent variant and does not change the amino acid, reducing the probability that this variant is disease causing. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.29
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: -16

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs908321451; hg19: chr19-13414597;