rs16022

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001127222.2(CACNA1A):​c.2751G>C​(p.Glu917Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,592,562 control chromosomes in the GnomAD database, including 15,785 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E917E) has been classified as Benign.

Frequency

Genomes: 𝑓 0.12 ( 1247 hom., cov: 32)
Exomes 𝑓: 0.14 ( 14538 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

1
17

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12O:1

Conservation

PhyloP100: 0.00200
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 Benign. Variant got -19 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=0.0017104447).
BP6
Variant 19-13298882-C-G is Benign according to our data. Variant chr19-13298882-C-G is described in ClinVar as [Benign]. Clinvar id is 68426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298882-C-G is described in Lovd as [Benign]. Variant chr19-13298882-C-G is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1ANM_001127222.2 linkuse as main transcriptc.2751G>C p.Glu917Asp 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 linkuse as main transcriptc.2751G>C p.Glu917Asp missense_variant 19/471 NM_001127222.2 ENSP00000353362.5 O00555-8
CACNA1AENST00000638029.1 linkuse as main transcriptc.2763G>C p.Glu921Asp missense_variant 19/485 ENSP00000489829.1 A0A087WW63
CACNA1AENST00000573710.7 linkuse as main transcriptc.2757G>C p.Glu919Asp missense_variant 19/475 ENSP00000460092.3 A0A1C7CYY9
CACNA1AENST00000635727.1 linkuse as main transcriptc.2754G>C p.Glu918Asp missense_variant 19/475 ENSP00000490001.1 A0A1B0GU81
CACNA1AENST00000637769.1 linkuse as main transcriptc.2754G>C p.Glu918Asp missense_variant 19/471 ENSP00000489778.1 A0A1B0GTN7
CACNA1AENST00000636012.1 linkuse as main transcriptc.2754G>C p.Glu918Asp missense_variant 19/465 ENSP00000490223.1 A0A1B0GUS3
CACNA1AENST00000637736.1 linkuse as main transcriptc.2613G>C p.Glu871Asp missense_variant 18/465 ENSP00000489861.1 A0A1B0GTW2
CACNA1AENST00000636389.1 linkuse as main transcriptc.2754G>C p.Glu918Asp missense_variant 19/475 ENSP00000489992.1 A0A1B0GU74
CACNA1AENST00000637432.1 linkuse as main transcriptc.2763G>C p.Glu921Asp missense_variant 19/485 ENSP00000490617.1 O00555-2
CACNA1AENST00000636549.1 linkuse as main transcriptc.2754G>C p.Glu918Asp missense_variant 19/485 ENSP00000490578.1 B5TYJ1
CACNA1AENST00000637927.1 linkuse as main transcriptc.2757G>C p.Glu919Asp missense_variant 19/475 ENSP00000489715.1 A0A1B0GTI4
CACNA1AENST00000635895.1 linkuse as main transcriptc.2754G>C p.Glu918Asp missense_variant 19/475 ENSP00000490323.1 A0A384DVW2
CACNA1AENST00000638009.2 linkuse as main transcriptc.2754G>C p.Glu918Asp missense_variant 19/471 ENSP00000489913.1 O00555-3
CACNA1AENST00000637276.1 linkuse as main transcriptc.2754G>C p.Glu918Asp missense_variant 19/465 ENSP00000489777.1 O00555-5

Frequencies

GnomAD3 genomes
AF:
0.122
AC:
18593
AN:
152102
Hom.:
1247
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0721
Gnomad AMI
AF:
0.162
Gnomad AMR
AF:
0.136
Gnomad ASJ
AF:
0.154
Gnomad EAS
AF:
0.123
Gnomad SAS
AF:
0.120
Gnomad FIN
AF:
0.123
Gnomad MID
AF:
0.162
Gnomad NFE
AF:
0.147
Gnomad OTH
AF:
0.140
GnomAD3 exomes
AF:
0.126
AC:
27267
AN:
215748
Hom.:
1777
AF XY:
0.125
AC XY:
15073
AN XY:
120314
show subpopulations
Gnomad AFR exome
AF:
0.0630
Gnomad AMR exome
AF:
0.137
Gnomad ASJ exome
AF:
0.151
Gnomad EAS exome
AF:
0.0982
Gnomad SAS exome
AF:
0.110
Gnomad FIN exome
AF:
0.112
Gnomad NFE exome
AF:
0.139
Gnomad OTH exome
AF:
0.139
GnomAD4 exome
AF:
0.140
AC:
201088
AN:
1440352
Hom.:
14538
Cov.:
33
AF XY:
0.139
AC XY:
99703
AN XY:
716648
show subpopulations
Gnomad4 AFR exome
AF:
0.0667
Gnomad4 AMR exome
AF:
0.141
Gnomad4 ASJ exome
AF:
0.153
Gnomad4 EAS exome
AF:
0.142
Gnomad4 SAS exome
AF:
0.115
Gnomad4 FIN exome
AF:
0.120
Gnomad4 NFE exome
AF:
0.144
Gnomad4 OTH exome
AF:
0.143
GnomAD4 genome
AF:
0.122
AC:
18601
AN:
152210
Hom.:
1247
Cov.:
32
AF XY:
0.121
AC XY:
9005
AN XY:
74422
show subpopulations
Gnomad4 AFR
AF:
0.0722
Gnomad4 AMR
AF:
0.136
Gnomad4 ASJ
AF:
0.154
Gnomad4 EAS
AF:
0.122
Gnomad4 SAS
AF:
0.120
Gnomad4 FIN
AF:
0.123
Gnomad4 NFE
AF:
0.147
Gnomad4 OTH
AF:
0.139
Alfa
AF:
0.0877
Hom.:
185
Bravo
AF:
0.121
TwinsUK
AF:
0.135
AC:
501
ALSPAC
AF:
0.141
AC:
545
ESP6500AA
AF:
0.0585
AC:
206
ESP6500EA
AF:
0.116
AC:
883
ExAC
AF:
0.119
AC:
13837
Asia WGS
AF:
0.115
AC:
397
AN:
3462

ClinVar

Significance: Benign
Submissions summary: Benign:12Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:9
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsMay 03, 2021- -
Benign, criteria provided, single submitterclinical testingUnidad de Genómica Garrahan, Hospital de Pediatría GarrahanJul 15, 2024This variant is classified as Benign based on local population frequency. This variant was detected in 30% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 28. Only high quality variants are reported. -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 18, 2014- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Likely benign, no assertion criteria providedclinical testingGenetic Services Laboratory, University of Chicago-Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingGeneDxJan 05, 2016This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
not provided Benign:1Other:1
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
not provided, no classification providedliterature onlyUniProtKB/Swiss-Prot-- -
Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 16, 2016This alteration is classified as 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
0.083
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
11
DANN
Benign
0.58
DEOGEN2
Benign
0.024
.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen
Benign
-0.90
Eigen_PC
Benign
-0.82
FATHMM_MKL
Benign
0.032
N
LIST_S2
Benign
0.59
T;T;T;T;T;T;T;T;.;T;T;T;T;T;T
MetaRNN
Benign
0.0017
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.49
T
MutationAssessor
Benign
0.90
.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-0.66
.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Benign
0.25
Sift
Benign
0.43
.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Benign
0.11
T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.013
MutPred
0.17
.;.;Gain of MoRF binding (P = 0.2255);Gain of MoRF binding (P = 0.2255);Gain of MoRF binding (P = 0.2255);.;Gain of MoRF binding (P = 0.2255);.;.;Gain of MoRF binding (P = 0.2255);Gain of MoRF binding (P = 0.2255);.;Gain of MoRF binding (P = 0.2255);.;Gain of MoRF binding (P = 0.2255);
MPC
2.0
ClinPred
0.0072
T
GERP RS
1.5
Varity_R
0.045
gMVP
0.37

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: rs16022; hg19: chr19-13409696; COSMIC: COSV64192678; API