rs756972061

chr19-13308251-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP7

The NM_001127222.2(CACNA1A):c.1782G>A(p.Lys594=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,611,524 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.9480
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.68

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.2).
• BP7: Synonymous conserved (PhyloP=2.68 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.1782G>A	p.Lys594=	splice_region_variant, synonymous_variant	14/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.1782G>A	p.Lys594=	splice_region_variant, synonymous_variant	14/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.0000162 AC: 4 AN: 247128 Hom.: 0 AF XY: 0.0000298 AC XY: 4 AN XY: 134122

Gnomad AFR exome AF: 0.00

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: 0.0000357

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1459396 Hom.: 0 Cov.: 32 AF XY: 0.0000152 AC XY: 11 AN XY: 725718

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: 0.0000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

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

Alfa AF: 0.0000451 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 05, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 21, 2023

Variant summary: CACNA1A c.1785G>A (p.Lys595Lys) does not directly result in a change to the encoded protein sequence, however, it alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a canonical 3' acceptor site and three predict the variant weakens the canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 247128 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1785G>A in individuals affected with Epileptic Encephalopathy, Early Infantile, 42 and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified it as VUS (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 09, 2023

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 is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 377265). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. This variant is present in population databases (rs756972061, gnomAD 0.003%). This sequence change affects codon 595 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
Cadd	Benign	17
Dann	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.050		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: rs756972061; hg19: chr19-13419065;