rs374664760

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001127222.2(CACNA1A):​c.2678G>C​(p.Arg893Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R893Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

CACNA1A
NM_001127222.2 missense

Scores

2
5
12

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.503
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the CACNA1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. Gene score misZ: 5.7845 (above the threshold of 3.09). Trascript score misZ: 3.9354 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.2595644).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1ANM_001127222.2 linkc.2678G>C p.Arg893Pro missense_variant Exon 19 of 47 ENST00000360228.11 NP_001120694.1 O00555-8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CACNA1AENST00000360228.11 linkc.2678G>C p.Arg893Pro missense_variant Exon 19 of 47 1 NM_001127222.2 ENSP00000353362.5 O00555-8
CACNA1AENST00000638029.1 linkc.2690G>C p.Arg897Pro missense_variant Exon 19 of 48 5 ENSP00000489829.1 A0A087WW63
CACNA1AENST00000573710.7 linkc.2684G>C p.Arg895Pro missense_variant Exon 19 of 47 5 ENSP00000460092.3 A0A1C7CYY9
CACNA1AENST00000635727.1 linkc.2681G>C p.Arg894Pro missense_variant Exon 19 of 47 5 ENSP00000490001.1 A0A1B0GU81
CACNA1AENST00000637769.1 linkc.2681G>C p.Arg894Pro missense_variant Exon 19 of 47 1 ENSP00000489778.1 A0A1B0GTN7
CACNA1AENST00000636012.1 linkc.2681G>C p.Arg894Pro missense_variant Exon 19 of 46 5 ENSP00000490223.1 A0A1B0GUS3
CACNA1AENST00000637736.1 linkc.2540G>C p.Arg847Pro missense_variant Exon 18 of 46 5 ENSP00000489861.1 A0A1B0GTW2
CACNA1AENST00000636389.1 linkc.2681G>C p.Arg894Pro missense_variant Exon 19 of 47 5 ENSP00000489992.1 A0A1B0GU74
CACNA1AENST00000637432.1 linkc.2690G>C p.Arg897Pro missense_variant Exon 19 of 48 5 ENSP00000490617.1 O00555-2
CACNA1AENST00000636549.1 linkc.2681G>C p.Arg894Pro missense_variant Exon 19 of 48 5 ENSP00000490578.1 B5TYJ1
CACNA1AENST00000637927.1 linkc.2684G>C p.Arg895Pro missense_variant Exon 19 of 47 5 ENSP00000489715.1 A0A1B0GTI4
CACNA1AENST00000635895.1 linkc.2681G>C p.Arg894Pro missense_variant Exon 19 of 47 5 ENSP00000490323.1 A0A384DVW2
CACNA1AENST00000638009.2 linkc.2681G>C p.Arg894Pro missense_variant Exon 19 of 47 1 ENSP00000489913.1 O00555-3
CACNA1AENST00000637276.1 linkc.2681G>C p.Arg894Pro missense_variant Exon 19 of 46 5 ENSP00000489777.1 O00555-5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
-0.080
CADD
Benign
23
DANN
Benign
0.93
DEOGEN2
Benign
0.031
.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen
Benign
-0.83
Eigen_PC
Benign
-0.83
FATHMM_MKL
Benign
0.086
N
LIST_S2
Uncertain
0.89
D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.98
D
MetaRNN
Benign
0.26
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.11
D
MutationAssessor
Benign
1.1
.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Benign
-2.0
.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Uncertain
0.36
Sift
Benign
0.097
.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Benign
0.26
T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.34
MutPred
0.13
.;.;Loss of solvent accessibility (P = 0.0703);Loss of solvent accessibility (P = 0.0703);Loss of solvent accessibility (P = 0.0703);.;Loss of solvent accessibility (P = 0.0703);.;.;Loss of solvent accessibility (P = 0.0703);Loss of solvent accessibility (P = 0.0703);.;Loss of solvent accessibility (P = 0.0703);.;Loss of solvent accessibility (P = 0.0703);
MVP
0.84
MPC
2.3
ClinPred
0.30
T
GERP RS
1.6
Varity_R
0.45
gMVP
0.68

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs374664760; hg19: chr19-13409769; API