NM_001127222.2:c.5400+3G>A

Variant names:

• chr19-13231707-C-T
• rs1034627495
• NM_001127222.2:c.5400+3G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001127222.2(CACNA1A):​c.5400+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,608,324 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 splice_region, intron
• Scores: Splicing: ADA: 0.00003035
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.732

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5400+3G>A		splice_region_variant, intron_variant	Intron 35 of 46	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.5400+3G>A		splice_region_variant, intron_variant	Intron 35 of 46	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5418+3G>A		splice_region_variant, intron_variant	Intron 36 of 47	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.5406+3G>A		splice_region_variant, intron_variant	Intron 35 of 46	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.5403+3G>A		splice_region_variant, intron_variant	Intron 35 of 46	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.5403+3G>A		splice_region_variant, intron_variant	Intron 35 of 46	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.5403+3G>A		splice_region_variant, intron_variant	Intron 35 of 45	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.5262+3G>A		splice_region_variant, intron_variant	Intron 34 of 45	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5403+3G>A		splice_region_variant, intron_variant	Intron 35 of 46	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.5418+3G>A		splice_region_variant, intron_variant	Intron 36 of 47	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5409+3G>A		splice_region_variant, intron_variant	Intron 36 of 47	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.5406+3G>A		splice_region_variant, intron_variant	Intron 35 of 46	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.5403+3G>A		splice_region_variant, intron_variant	Intron 35 of 46	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.5403+3G>A		splice_region_variant, intron_variant	Intron 35 of 46	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.5403+3G>A		splice_region_variant, intron_variant	Intron 35 of 45	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.27+3G>A		splice_region_variant, intron_variant	Intron 1 of 9	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152188 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000965

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: 0.00000418 AC: 1 AN: 239470 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 129940

Gnomad AFR exome AF: 0.0000685

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456136 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723916

Gnomad4 AFR exome AF: 0.0000300

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152188 Hom.: 0 Cov.: 31 AF XY: 0.0000403 AC XY: 3 AN XY: 74364

Gnomad4 AFR AF: 0.0000965

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

Bravo AF: 0.0000113

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

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 35 of the CACNA1A gene. It does not directly change the encoded amino acid sequence of the CACNA1A protein. It affects a nucleotide within the consensus splice site. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 476265). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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	-0.34
CADD	Benign	19
DANN	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.0020
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: rs1034627495; hg19: chr19-13342521;