19-13303585-G-T

Position:

• chr19-13303585-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001127222.2(CACNA1A):​c.2133C>A​(p.Ile711Ile) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000497 in 1,610,972 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: 𝑓 0.0000066 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2133C>A	p.Ile711Ile	synonymous_variant	17/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2133C>A	p.Ile711Ile	synonymous_variant	17/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2136C>A	p.Ile712Ile	synonymous_variant	17/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2139C>A	p.Ile713Ile	synonymous_variant	17/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2136C>A	p.Ile712Ile	synonymous_variant	17/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2136C>A	p.Ile712Ile	synonymous_variant	17/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2136C>A	p.Ile712Ile	synonymous_variant	17/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.1995C>A	p.Ile665Ile	synonymous_variant	16/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2136C>A	p.Ile712Ile	synonymous_variant	17/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2136C>A	p.Ile712Ile	synonymous_variant	17/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2136C>A	p.Ile712Ile	synonymous_variant	17/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2139C>A	p.Ile713Ile	synonymous_variant	17/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2136C>A	p.Ile712Ile	synonymous_variant	17/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2136C>A	p.Ile712Ile	synonymous_variant	17/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2136C>A	p.Ile712Ile	synonymous_variant	17/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151874 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459098 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 725572

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: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151874 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 74156

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Sep 24, 2023

This sequence change affects codon 712 of the CACNA1A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CACNA1A protein. This variant is not present in population databases (gnomAD no frequency). 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: 578805). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	-0.21
CADD	Benign	10
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs764839814; hg19: chr19-13414399;