rs1057518292

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001127222.2(CACNA1A):​c.2857G>C​(p.Gly953Arg) 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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Consequence

CACNA1A
NM_001127222.2 missense

Scores

2
3
14

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.32
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 2 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: 3.9354 (greater than threshold 3.09). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. GenCC has associacion of the 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.28657246).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1ANM_001127222.2 linkc.2857G>C p.Gly953Arg missense_variant 19/47 ENST00000360228.11 NP_001120694.1 O00555-8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CACNA1AENST00000360228.11 linkc.2857G>C p.Gly953Arg missense_variant 19/471 NM_001127222.2 ENSP00000353362.5 O00555-8
CACNA1AENST00000638029.1 linkc.2869G>C p.Gly957Arg missense_variant 19/485 ENSP00000489829.1 A0A087WW63
CACNA1AENST00000573710.7 linkc.2863G>C p.Gly955Arg missense_variant 19/475 ENSP00000460092.3 A0A1C7CYY9
CACNA1AENST00000635727.1 linkc.2860G>C p.Gly954Arg missense_variant 19/475 ENSP00000490001.1 A0A1B0GU81
CACNA1AENST00000637769.1 linkc.2860G>C p.Gly954Arg missense_variant 19/471 ENSP00000489778.1 A0A1B0GTN7
CACNA1AENST00000636012.1 linkc.2860G>C p.Gly954Arg missense_variant 19/465 ENSP00000490223.1 A0A1B0GUS3
CACNA1AENST00000637736.1 linkc.2719G>C p.Gly907Arg missense_variant 18/465 ENSP00000489861.1 A0A1B0GTW2
CACNA1AENST00000636389.1 linkc.2860G>C p.Gly954Arg missense_variant 19/475 ENSP00000489992.1 A0A1B0GU74
CACNA1AENST00000637432.1 linkc.2869G>C p.Gly957Arg missense_variant 19/485 ENSP00000490617.1 O00555-2
CACNA1AENST00000636549.1 linkc.2860G>C p.Gly954Arg missense_variant 19/485 ENSP00000490578.1 B5TYJ1
CACNA1AENST00000637927.1 linkc.2863G>C p.Gly955Arg missense_variant 19/475 ENSP00000489715.1 A0A1B0GTI4
CACNA1AENST00000635895.1 linkc.2860G>C p.Gly954Arg missense_variant 19/475 ENSP00000490323.1 A0A384DVW2
CACNA1AENST00000638009.2 linkc.2860G>C p.Gly954Arg missense_variant 19/471 ENSP00000489913.1 O00555-3
CACNA1AENST00000637276.1 linkc.2860G>C p.Gly954Arg missense_variant 19/465 ENSP00000489777.1 O00555-5

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Uncertain
0.099
D
BayesDel_noAF
Benign
-0.090
CADD
Benign
18
DANN
Benign
0.94
DEOGEN2
Benign
0.0025
.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen
Benign
-0.62
Eigen_PC
Benign
-0.52
FATHMM_MKL
Benign
0.64
D
LIST_S2
Benign
0.81
T;T;T;T;T;T;T;T;.;T;T;T;T;T;T
M_CAP
Pathogenic
0.94
D
MetaRNN
Benign
0.29
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.20
T
MutationAssessor
Benign
-0.18
.;.;.;.;N;.;.;.;.;.;.;.;N;.;.
PrimateAI
Pathogenic
0.92
D
PROVEAN
Benign
-0.25
.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Uncertain
0.42
Sift
Benign
0.91
.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Benign
0.80
T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.47
MutPred
0.26
.;.;Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);.;Gain of helix (P = 0.0034);.;.;Gain of helix (P = 0.0034);Gain of helix (P = 0.0034);.;Gain of helix (P = 0.0034);.;Gain of helix (P = 0.0034);
MVP
0.91
MPC
2.5
ClinPred
0.21
T
GERP RS
4.2
Varity_R
0.055
gMVP
0.46

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: rs1057518292; hg19: chr19-13409590; API