19-13277122-G-A

Position:

• chr19-13277122-G-A

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]

CACNA1A (HGNC:):

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/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.3829C>T	p.Arg1277*	stop_gained	23/47	ENST00000360228.11	NP_001120694.1

Ensembl

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 27, 2001	- -
Pathogenic, no assertion criteria provided	clinical testing	E. Rossignol Lab, CHU Ste-Justine, Universite de Montreal	Nov 25, 2014	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 16, 2021

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects CACNA1A protein function (PMID: 11742003). This variant has been observed in individual(s) with CACNA1A-related conditions (PMID: 9600739, 25784583, 25735478). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 8506). This variant is also known as c.4110C>T (p.Arg1279*). This variant is not present in population databases (ExAC no frequency). 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). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 22, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 08, 2024

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;