rs775079932

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The ENST00000360228.11(CACNA1A):​c.3175C>T​(p.Pro1059Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,613,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1059T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

CACNA1A
ENST00000360228.11 missense

Scores

1
2
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 2.82
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

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). 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.10547599).
BP6
Variant 19-13286881-G-A is Benign according to our data. Variant chr19-13286881-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 585563.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}.
BS2
High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1ANM_001127222.2 linkuse as main transcriptc.3175C>T p.Pro1059Ser missense_variant 20/47 ENST00000360228.11 NP_001120694.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CACNA1AENST00000360228.11 linkuse as main transcriptc.3175C>T p.Pro1059Ser missense_variant 20/471 NM_001127222.2 ENSP00000353362 O00555-8

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152220
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000447
AC:
11
AN:
246036
Hom.:
0
AF XY:
0.0000373
AC XY:
5
AN XY:
134204
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000901
Gnomad OTH exome
AF:
0.000167
GnomAD4 exome
AF:
0.0000493
AC:
72
AN:
1461320
Hom.:
0
Cov.:
35
AF XY:
0.0000509
AC XY:
37
AN XY:
726952
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000189
Gnomad4 NFE exome
AF:
0.0000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152220
Hom.:
0
Cov.:
31
AF XY:
0.0000403
AC XY:
3
AN XY:
74366
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000987
Hom.:
0
Bravo
AF:
0.0000302
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000499
AC:
6
EpiCase
AF:
0.000109
EpiControl
AF:
0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxApr 02, 2020This variant is associated with the following publications: (PMID: 31731261) -
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsDec 30, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2023- -
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 18, 2023- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 04, 2019This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.20
CADD
Benign
21
DANN
Benign
0.96
DEOGEN2
Benign
0.0029
.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen
Benign
-0.33
Eigen_PC
Benign
-0.091
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.86
D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.36
D
MetaRNN
Benign
0.11
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.56
T
MutationAssessor
Benign
0.71
.;.;.;.;N;.;.;.;.;.;.;.;N;.;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-1.0
.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Benign
0.23
Sift
Benign
1.0
.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Benign
0.90
T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.29
MVP
0.62
MPC
0.013
ClinPred
0.069
T
GERP RS
5.2
Varity_R
0.085
gMVP
0.28

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: rs775079932; hg19: chr19-13397695; API