rs779221807

Variant names:

• chr19-13212204-G-A
• rs779221807
• NM_001127222.2:c.6202C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-13212204-G-A
• chr19-13212204-G-C
• chr19-13212204-G-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.6202C>T​(p.Arg2068*) 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: 34)
• Consequence: CACNA1A NM_001127222.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.88

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 19-13212204-G-A is Pathogenic according to our data. Variant chr19-13212204-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 583270.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.6202C>T	p.Arg2068*	stop_gained	Exon 43 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6202C>T	p.Arg2068*	stop_gained	Exon 43 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6220C>T	p.Arg2074*	stop_gained	Exon 44 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6208C>T	p.Arg2070*	stop_gained	Exon 43 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6205C>T	p.Arg2069*	stop_gained	Exon 43 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6205C>T	p.Arg2069*	stop_gained	Exon 43 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6205C>T	p.Arg2069*	stop_gained	Exon 43 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6064C>T	p.Arg2022*	stop_gained	Exon 42 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6205C>T	p.Arg2069*	stop_gained	Exon 43 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6220C>T	p.Arg2074*	stop_gained	Exon 44 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6211C>T	p.Arg2071*	stop_gained	Exon 44 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6208C>T	p.Arg2070*	stop_gained	Exon 43 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6205C>T	p.Arg2069*	stop_gained	Exon 43 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6205C>T	p.Arg2069*	stop_gained	Exon 43 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6205C>T	p.Arg2069*	stop_gained	Exon 43 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*504C>T		non_coding_transcript_exon_variant	Exon 8 of 10	5		ENSP00000490190.2
CACNA1A	ENST00000636768.1	n.*504C>T		3_prime_UTR_variant	Exon 8 of 10	5		ENSP00000490190.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Mar 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This sequence change creates a premature translational stop signal (p.Arg2069*) 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 clinical features of CACNA1A-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 583270). -

not provided Pathogenic:1

Aug 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.74	D
Vest4		0.93
GERP RS		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs779221807; hg19: chr19-13323018;