rs121908244

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_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

Scores

8
3
2

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 9.20
Variant links:
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]

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ACMG classification

Classification made for transcript

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
CACNA1ANM_001127222.2 linkuse as main transcriptc.5529-1195T>C intron_variant ENST00000360228.11 NP_001120694.1 O00555-8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CACNA1AENST00000573710.7 linkuse as main transcriptc.5608T>C p.Cys1870Arg missense_variant 37/475 ENSP00000460092.3 A0A1C7CYY9
CACNA1AENST00000637769.1 linkuse as main transcriptc.5605T>C p.Cys1869Arg missense_variant 37/471 ENSP00000489778.1 A0A1B0GTN7
CACNA1AENST00000637736.1 linkuse as main transcriptc.5464T>C p.Cys1822Arg missense_variant 36/465 ENSP00000489861.1 A0A1B0GTW2
CACNA1AENST00000636389.1 linkuse as main transcriptc.5605T>C p.Cys1869Arg missense_variant 37/475 ENSP00000489992.1 A0A1B0GU74
CACNA1AENST00000637927.1 linkuse as main transcriptc.5608T>C p.Cys1870Arg missense_variant 37/475 ENSP00000489715.1 A0A1B0GTI4
CACNA1AENST00000638009.2 linkuse as main transcriptc.5605T>C p.Cys1869Arg missense_variant 37/471 ENSP00000489913.1 O00555-3
CACNA1AENST00000360228.11 linkuse as main transcriptc.5529-1195T>C intron_variant 1 NM_001127222.2 ENSP00000353362.5 O00555-8
CACNA1AENST00000638029.1 linkuse as main transcriptc.5547-1195T>C intron_variant 5 ENSP00000489829.1 A0A087WW63
CACNA1AENST00000635727.1 linkuse as main transcriptc.5532-1195T>C intron_variant 5 ENSP00000490001.1 A0A1B0GU81
CACNA1AENST00000636012.1 linkuse as main transcriptc.5532-1195T>C intron_variant 5 ENSP00000490223.1 A0A1B0GUS3
CACNA1AENST00000637432.1 linkuse as main transcriptc.5547-1195T>C intron_variant 5 ENSP00000490617.1 O00555-2
CACNA1AENST00000636549.1 linkuse as main transcriptc.5538-1195T>C intron_variant 5 ENSP00000490578.1 B5TYJ1
CACNA1AENST00000635895.1 linkuse as main transcriptc.5532-1195T>C intron_variant 5 ENSP00000490323.1 A0A384DVW2
CACNA1AENST00000637276.1 linkuse as main transcriptc.5532-1195T>C intron_variant 5 ENSP00000489777.1 O00555-5
CACNA1AENST00000636768.1 linkuse as main transcriptn.155+1360T>C intron_variant 5 ENSP00000490190.2 A0A1B0GUP3

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
LINK: link

Submissions by phenotype

Episodic ataxia type 2 Other:1
not provided, no classification providedliterature onlyUniProtKB/Swiss-Prot-- -

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121908244; hg19: chr19-13339536; API