rs372970603

Variant names:

• chr19-13303761-G-A
• rs372970603
• NM_001127222.2:c.2104+6C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001127222.2(CACNA1A):​c.2104+6C>T variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,601,840 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 0.000092 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 splice_region, intron
• Scores: Splicing: ADA: 0.00002712
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.93

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 -4 ACMG points.

• BS2: High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2104+6C>T		splice_region_variant, intron_variant	Intron 16 of 46	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2104+6C>T		splice_region_variant, intron_variant	Intron 16 of 46	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2107+6C>T		splice_region_variant, intron_variant	Intron 16 of 47	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2110+6C>T		splice_region_variant, intron_variant	Intron 16 of 46	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2107+6C>T		splice_region_variant, intron_variant	Intron 16 of 46	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2107+6C>T		splice_region_variant, intron_variant	Intron 16 of 46	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2107+6C>T		splice_region_variant, intron_variant	Intron 16 of 45	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.1966+6C>T		splice_region_variant, intron_variant	Intron 15 of 45	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2107+6C>T		splice_region_variant, intron_variant	Intron 16 of 46	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2107+6C>T		splice_region_variant, intron_variant	Intron 16 of 47	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2107+6C>T		splice_region_variant, intron_variant	Intron 16 of 47	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2110+6C>T		splice_region_variant, intron_variant	Intron 16 of 46	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2107+6C>T		splice_region_variant, intron_variant	Intron 16 of 46	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2107+6C>T		splice_region_variant, intron_variant	Intron 16 of 46	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2107+6C>T		splice_region_variant, intron_variant	Intron 16 of 45	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152002 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000321 AC: 8 AN: 249278 Hom.: 0 AF XY: 0.0000518 AC XY: 7 AN XY: 135238

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000966 AC: 14 AN: 1449838 Hom.: 0 Cov.: 29 AF XY: 0.00000831 AC XY: 6 AN XY: 722148

Gnomad4 AFR exome AF: 0.000301

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.08e-7

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 152002 Hom.: 0 Cov.: 29 AF XY: 0.000108 AC XY: 8 AN XY: 74232

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000869

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

May 02, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge -

Aug 11, 2023

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools yielded inconclusive predictions regarding the effect of this variant on RNA splicing. -

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

Aug 17, 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 16 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. This variant is present in population databases (rs372970603, gnomAD 0.04%). 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: 446907). 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 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	-0.39
CADD	Benign	18
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
SpliceAI score (max)		0.62		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.62		Position offset: 6

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

Publications

LitVar

Other links and lift over

dbSNP: rs372970603; hg19: chr19-13414575;