rs886039668

Variant names:

• chr19-13317307-G-A
• rs886039668
• NM_001127222.2:c.1360C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001127222.2(CACNA1A):​c.1360C>T​(p.Arg454*) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R454R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1A NM_001127222.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.42
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• episodic ataxia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
• developmental and epileptic encephalopathy, 42

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• migraine, familial hemiplegic, 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• spinocerebellar ataxia type 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• benign paroxysmal torticollis of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial or sporadic hemiplegic migraine

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000306107 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 19-13317307-G-A is Pathogenic according to our data. Variant chr19-13317307-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 265613.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.1360C>T	p.Arg454*	stop_gained	Exon 11 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.1360C>T	p.Arg454*	stop_gained	Exon 11 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.1363C>T	p.Arg455*	stop_gained	Exon 11 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.1366C>T	p.Arg456*	stop_gained	Exon 11 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.1363C>T	p.Arg455*	stop_gained	Exon 11 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.1363C>T	p.Arg455*	stop_gained	Exon 11 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.1363C>T	p.Arg455*	stop_gained	Exon 11 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.1222C>T	p.Arg408*	stop_gained	Exon 10 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.1363C>T	p.Arg455*	stop_gained	Exon 11 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.1363C>T	p.Arg455*	stop_gained	Exon 11 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.1363C>T	p.Arg455*	stop_gained	Exon 11 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.1366C>T	p.Arg456*	stop_gained	Exon 11 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.1363C>T	p.Arg455*	stop_gained	Exon 11 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.1363C>T	p.Arg455*	stop_gained	Exon 11 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.1363C>T	p.Arg455*	stop_gained	Exon 11 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2	n.1363C>T		non_coding_transcript_exon_variant	Exon 11 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1	n.1360C>T		non_coding_transcript_exon_variant	Exon 11 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1449108 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 717832

African (AFR) AF: 0.00 AC: 0 AN: 33280

American (AMR) AF: 0.00 AC: 0 AN: 44478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39338

South Asian (SAS) AF: 0.00 AC: 0 AN: 85946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101336

Other (OTH) AF: 0.00 AC: 0 AN: 59758

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Oct 26, 2017

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 23183922, 38699371, 21734179, 10371528, 27250579, 25735478, 19486177, 37422902) -

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

Oct 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.Arg455*) 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 episodic ataxia (PMID: 23183922). ClinVar contains an entry for this variant (Variation ID: 265613). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		3.4
Vest4		0.96
GERP RS		4.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs886039668; hg19: chr19-13428121; COSMIC: COSV100800475; COSMIC: COSV100800475;