NM_001127222.2:c.631+5G>A

Variant names:

• chr19-13371683-C-T
• rs786200963
• NM_001127222.2:c.631+5G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001127222.2(CACNA1A):​c.631+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000000708 in 1,412,862 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 predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:3
• Conservation: PhyloP100: 7.01

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_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 19-13371683-C-T is Pathogenic according to our data. Variant chr19-13371683-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 187829.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.631+5G>A		splice_region_variant, intron_variant	Intron 4 of 46	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.631+5G>A		splice_region_variant, intron_variant	Intron 4 of 46	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.631+5G>A		splice_region_variant, intron_variant	Intron 4 of 47	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.631+5G>A		splice_region_variant, intron_variant	Intron 4 of 46	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.631+5G>A		splice_region_variant, intron_variant	Intron 4 of 46	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.631+5G>A		splice_region_variant, intron_variant	Intron 4 of 46	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.631+5G>A		splice_region_variant, intron_variant	Intron 4 of 45	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.490+5G>A		splice_region_variant, intron_variant	Intron 3 of 45	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.631+5G>A		splice_region_variant, intron_variant	Intron 4 of 46	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.631+5G>A		splice_region_variant, intron_variant	Intron 4 of 47	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.631+5G>A		splice_region_variant, intron_variant	Intron 4 of 47	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.631+5G>A		splice_region_variant, intron_variant	Intron 4 of 46	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.631+5G>A		splice_region_variant, intron_variant	Intron 4 of 46	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.631+5G>A		splice_region_variant, intron_variant	Intron 4 of 46	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.631+5G>A		splice_region_variant, intron_variant	Intron 4 of 45	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1412862 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 698558

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: 9.21e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

CACNA1A-related disorder Pathogenic:3

Jun 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CACNA1A c.631+5G>A variant is predicted to interfere with splicing. This variant was reported in three patients with episodic ataxia from two different families with RNA studies finding this variant results in skipping of exon 4 resulting in premature protein termination (described as c.868+5G>A, Damaj et al. 2015. PubMed ID: 25735478; Riant et al. 2023. PubMed ID: 37177896). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

May 10, 2024

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 31, 2021

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CACNA1A c.631+5G>A variant, also referred to as c.868+5G>A in the literature, is a splice region variant that has been reported in one study, in which it was identified in a proband with episodic ataxia type 2 and in his affected mother (Damaj et al. 2015). Another variant at the same nucleotide position has also been reported in two individuals with CACNA1A-related disorders (Gur-Hartman et al. 2021). The c.631+5G>A variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence, the c.631+5G>A variant is classified as likely pathogenic for CACNA1A-related disorders. -

not provided Pathogenic:1 Uncertain:2

Nov 30, 2021

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 12, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intronic variant directly or indirectly altering the +5 splice site in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37177896, 25735478, 33349592) -

Apr 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Episodic ataxia type 2 Pathogenic:2

Nov 25, 2014

E. Rossignol Lab, CHU Ste-Justine, Universite de Montreal

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 14, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Nov 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 4 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. 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. 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. ClinVar contains an entry for this variant (Variation ID: 187829). This variant has been observed in individual(s) with episodic ataxia (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Benign	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.87		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.87		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs786200963; hg19: chr19-13482497;