rs121908244

Positions:

• chr19-13228722-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001127221.2(CACNA1A):​c.5605T>C​(p.Cys1869Arg) variant causes a missense change involving the alteration of a 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 not provided (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: CACNA1A NM_001127221.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 9.20

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1A. . Gene score misZ 5.7845 (greater than the threshold 3.09). Trascript score misZ 5.4429 (greater than threshold 3.09). GenCC has associacion of gene with benign paroxysmal torticollis of infancy, developmental and epileptic encephalopathy, 42, undetermined early-onset epileptic encephalopathy, episodic ataxia type 2, familial or sporadic hemiplegic migraine, spinocerebellar ataxia type 6, Lennox-Gastaut syndrome, migraine, familial hemiplegic, 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.5529-1195T>C		intron_variant		ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000573710.7	c.5608T>C	p.Cys1870Arg	missense_variant	37/47	5		ENSP00000460092.3
CACNA1A	ENST00000637769.1	c.5605T>C	p.Cys1869Arg	missense_variant	37/47	1		ENSP00000489778.1
CACNA1A	ENST00000637736.1	c.5464T>C	p.Cys1822Arg	missense_variant	36/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.5605T>C	p.Cys1869Arg	missense_variant	37/47	5		ENSP00000489992.1
CACNA1A	ENST00000637927.1	c.5608T>C	p.Cys1870Arg	missense_variant	37/47	5		ENSP00000489715.1
CACNA1A	ENST00000638009.2	c.5605T>C	p.Cys1869Arg	missense_variant	37/47	1		ENSP00000489913.1
CACNA1A	ENST00000360228.11	c.5529-1195T>C		intron_variant		1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.5547-1195T>C		intron_variant		5		ENSP00000489829.1
CACNA1A	ENST00000635727.1	c.5532-1195T>C		intron_variant		5		ENSP00000490001.1
CACNA1A	ENST00000636012.1	c.5532-1195T>C		intron_variant		5		ENSP00000490223.1
CACNA1A	ENST00000637432.1	c.5547-1195T>C		intron_variant		5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.5538-1195T>C		intron_variant		5		ENSP00000490578.1
CACNA1A	ENST00000635895.1	c.5532-1195T>C		intron_variant		5		ENSP00000490323.1
CACNA1A	ENST00000637276.1	c.5532-1195T>C		intron_variant		5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.155+1360T>C		intron_variant		5		ENSP00000490190.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 30

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Episodic ataxia type 2 Other:1

not provided, no classification provided

literature only

UniProtKB/Swiss-Prot

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.;.;.;.;.;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.30	D
Sift4G	Pathogenic	0.0	.;.;D;.;.;.;.;.
MutPred		0.60		Gain of disorder (P = 0.0059);Gain of disorder (P = 0.0059);.;.;Gain of disorder (P = 0.0059);.;.;.;
MVP		0.97
ClinPred		0.87	D
GERP RS		4.2

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: rs121908244; hg19: chr19-13339536;