NM_001127222.2:c.5891A>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_001127222.2(CACNA1A):​c.5891A>G​(p.Tyr1964Cys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

CACNA1A
NM_001127222.2 missense

Scores

8
9
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.68
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 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.926

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1ANM_001127222.2 linkc.5891A>G p.Tyr1964Cys missense_variant Exon 40 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.5891A>G p.Tyr1964Cys missense_variant Exon 40 of 47 1 NM_001127222.2 ENSP00000353362.5 O00555-8
CACNA1AENST00000638029.1 linkc.5909A>G p.Tyr1970Cys missense_variant Exon 41 of 48 5 ENSP00000489829.1 A0A087WW63
CACNA1AENST00000573710.7 linkc.5897A>G p.Tyr1966Cys missense_variant Exon 40 of 47 5 ENSP00000460092.3 A0A1C7CYY9
CACNA1AENST00000635727.1 linkc.5894A>G p.Tyr1965Cys missense_variant Exon 40 of 47 5 ENSP00000490001.1 A0A1B0GU81
CACNA1AENST00000637769.1 linkc.5894A>G p.Tyr1965Cys missense_variant Exon 40 of 47 1 ENSP00000489778.1 A0A1B0GTN7
CACNA1AENST00000636012.1 linkc.5894A>G p.Tyr1965Cys missense_variant Exon 40 of 46 5 ENSP00000490223.1 A0A1B0GUS3
CACNA1AENST00000637736.1 linkc.5753A>G p.Tyr1918Cys missense_variant Exon 39 of 46 5 ENSP00000489861.1 A0A1B0GTW2
CACNA1AENST00000636389.1 linkc.5894A>G p.Tyr1965Cys missense_variant Exon 40 of 47 5 ENSP00000489992.1 A0A1B0GU74
CACNA1AENST00000637432.1 linkc.5909A>G p.Tyr1970Cys missense_variant Exon 41 of 48 5 ENSP00000490617.1 O00555-2
CACNA1AENST00000636549.1 linkc.5900A>G p.Tyr1967Cys missense_variant Exon 41 of 48 5 ENSP00000490578.1 B5TYJ1
CACNA1AENST00000637927.1 linkc.5897A>G p.Tyr1966Cys missense_variant Exon 40 of 47 5 ENSP00000489715.1 A0A1B0GTI4
CACNA1AENST00000635895.1 linkc.5894A>G p.Tyr1965Cys missense_variant Exon 40 of 47 5 ENSP00000490323.1 A0A384DVW2
CACNA1AENST00000638009.2 linkc.5894A>G p.Tyr1965Cys missense_variant Exon 40 of 47 1 ENSP00000489913.1 O00555-3
CACNA1AENST00000637276.1 linkc.5894A>G p.Tyr1965Cys missense_variant Exon 40 of 46 5 ENSP00000489777.1 O00555-5
CACNA1AENST00000636768.1 linkn.*193A>G non_coding_transcript_exon_variant Exon 5 of 10 5 ENSP00000490190.2 A0A1B0GUP3
CACNA1AENST00000636768.1 linkn.*193A>G 3_prime_UTR_variant Exon 5 of 10 5 ENSP00000490190.2 A0A1B0GUP3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Feb 08, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.5894A>G (p.Y1965C) alteration is located in coding exon 40 of the CACNA1A gene. This alteration results from an A to G substitution at nucleotide position 5894, causing the tyrosine (Y) at amino acid position 1965 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1
Jun 27, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.17
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.14
.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.;.
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.97
D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.55
D
MetaRNN
Pathogenic
0.93
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.53
D
MutationAssessor
Uncertain
2.6
.;.;.;.;M;.;.;.;.;.;.;.;.;.;M;.;.;.;.
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-8.1
.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Pathogenic
0.84
Sift
Uncertain
0.016
.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Uncertain
0.035
D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.86
MutPred
0.73
.;.;Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);.;.;Loss of helix (P = 0.0558);.;.;.;Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);.;Loss of helix (P = 0.0558);.;.;.;.;
MVP
0.84
MPC
0.96
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.83
gMVP
0.92

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: rs1555732391; hg19: chr19-13325096; API