rs121909323

Variant names:

• chr19-13277122-G-A
• rs121909323
• NM_001127222.2:c.3829C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001127222.2(CACNA1A):​c.3829C>T​(p.Arg1277*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CACNA1A NM_001127222.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.21

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-13277122-G-A is Pathogenic according to our data. Variant chr19-13277122-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3829C>T	p.Arg1277*	stop_gained	Exon 23 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.3829C>T	p.Arg1277*	stop_gained	Exon 23 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.3841C>T	p.Arg1281*	stop_gained	Exon 23 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.3835C>T	p.Arg1279*	stop_gained	Exon 23 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.3832C>T	p.Arg1278*	stop_gained	Exon 23 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.3832C>T	p.Arg1278*	stop_gained	Exon 23 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.3832C>T	p.Arg1278*	stop_gained	Exon 23 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.3691C>T	p.Arg1231*	stop_gained	Exon 22 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.3832C>T	p.Arg1278*	stop_gained	Exon 23 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.3841C>T	p.Arg1281*	stop_gained	Exon 23 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.3832C>T	p.Arg1278*	stop_gained	Exon 23 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.3835C>T	p.Arg1279*	stop_gained	Exon 23 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.3832C>T	p.Arg1278*	stop_gained	Exon 23 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.3832C>T	p.Arg1278*	stop_gained	Exon 23 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.3832C>T	p.Arg1278*	stop_gained	Exon 23 of 46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Episodic ataxia type 2 Pathogenic:2

Nov 25, 2014

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 27, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Feb 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg1278*) in the CACNA1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CACNA1A are known to be pathogenic (PMID: 10371528, 19486177, 25735478, 27250579). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with CACNA1A-related conditions (PMID: 9600739, 25735478, 25784583). In at least one individual the variant was observed to be de novo. This variant is also known as c.4110C>T (p.Arg1279*). ClinVar contains an entry for this variant (Variation ID: 8506). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Dec 22, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect as variant leads to markedly decreased current densities compared to wild type (PMID: 11723274); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 11742003, 16306128, 28167673, 11723274, 32899500, 9600739, 25735478, 27667184, 25784583) -

CACNA1A-related complex neurodevelopmental disorder Pathogenic:1

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Type 2 episodic ataxia (MIM#108500) is mostly associated with loss of function, while familial hemiplegic migraine 1, with or without progressive cerebellar ataxia (MIM#141500) is associated with gain of function. Developmental and epileptic encephalopathy 42 (MIM#617106) is associated with both mechanisms, and spinocerebellar ataxia 6 (MIM#183086) is associated with CAG repeat expansion (OMIM, PMID: 25735478, 28566750, 31468518, 32116539). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Asymptomatic family members have been reported to carry the same variant as affected family members (PMID: 10408533, 30142438). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been reported for episodic ataxia, intellectual disability and/or epilepsy (PMID: 30142438, 32910250). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Many other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic in ClinVar and has been observed in two unrelated families with CACNA1A-related symptoms. (PMID: 25735478, 25784583). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	51
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.86	D
Vest4		0.96
GERP RS		3.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121909323; hg19: chr19-13387936; COSMIC: COSV64204750;