rs554393704

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001127222.2(CACNA1A):​c.6466C>T​(p.Arg2156Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,395,708 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 2 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

2
9
8

Clinical Significance

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

Conservation

PhyloP100: 0.490
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 -12 ACMG points.

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=0.01929152).
BP6
Variant 19-13209372-G-A is Benign according to our data. Variant chr19-13209372-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421928.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=3}.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000985 (15/152284) while in subpopulation SAS AF= 0.0029 (14/4830). AF 95% confidence interval is 0.00175. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1ANM_001127222.2 linkc.6466C>T p.Arg2156Cys missense_variant Exon 45 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.6466C>T p.Arg2156Cys missense_variant Exon 45 of 47 1 NM_001127222.2 ENSP00000353362.5 O00555-8
CACNA1AENST00000638029.1 linkc.6484C>T p.Arg2162Cys missense_variant Exon 46 of 48 5 ENSP00000489829.1 A0A087WW63
CACNA1AENST00000573710.7 linkc.6472C>T p.Arg2158Cys missense_variant Exon 45 of 47 5 ENSP00000460092.3 A0A1C7CYY9
CACNA1AENST00000635727.1 linkc.6469C>T p.Arg2157Cys missense_variant Exon 45 of 47 5 ENSP00000490001.1 A0A1B0GU81
CACNA1AENST00000637769.1 linkc.6469C>T p.Arg2157Cys missense_variant Exon 45 of 47 1 ENSP00000489778.1 A0A1B0GTN7
CACNA1AENST00000636012.1 linkc.6433C>T p.Arg2145Cys missense_variant Exon 44 of 46 5 ENSP00000490223.1 A0A1B0GUS3
CACNA1AENST00000637736.1 linkc.6328C>T p.Arg2110Cys missense_variant Exon 44 of 46 5 ENSP00000489861.1 A0A1B0GTW2
CACNA1AENST00000636389.1 linkc.6469C>T p.Arg2157Cys missense_variant Exon 45 of 47 5 ENSP00000489992.1 A0A1B0GU74
CACNA1AENST00000637432.1 linkc.6484C>T p.Arg2162Cys missense_variant Exon 46 of 48 5 ENSP00000490617.1 O00555-2
CACNA1AENST00000636549.1 linkc.6475C>T p.Arg2159Cys missense_variant Exon 46 of 48 5 ENSP00000490578.1 B5TYJ1
CACNA1AENST00000637927.1 linkc.6472C>T p.Arg2158Cys missense_variant Exon 45 of 47 5 ENSP00000489715.1 A0A1B0GTI4
CACNA1AENST00000635895.1 linkc.6469C>T p.Arg2157Cys missense_variant Exon 45 of 47 5 ENSP00000490323.1 A0A384DVW2
CACNA1AENST00000638009.2 linkc.6469C>T p.Arg2157Cys missense_variant Exon 45 of 47 1 ENSP00000489913.1 O00555-3
CACNA1AENST00000637276.1 linkc.6433C>T p.Arg2145Cys missense_variant Exon 44 of 46 5 ENSP00000489777.1 O00555-5
CACNA1AENST00000636768.1 linkn.*732C>T non_coding_transcript_exon_variant Exon 9 of 10 5 ENSP00000490190.2 A0A1B0GUP3
CACNA1AENST00000636768.1 linkn.*732C>T 3_prime_UTR_variant Exon 9 of 10 5 ENSP00000490190.2 A0A1B0GUP3

Frequencies

GnomAD3 genomes
AF:
0.0000986
AC:
15
AN:
152166
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00290
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000299
AC:
15
AN:
50246
Hom.:
0
AF XY:
0.000392
AC XY:
10
AN XY:
25528
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000169
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00264
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000537
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000106
AC:
132
AN:
1243424
Hom.:
2
Cov.:
32
AF XY:
0.000165
AC XY:
99
AN XY:
600646
show subpopulations
Gnomad4 AFR exome
AF:
0.0000386
Gnomad4 AMR exome
AF:
0.0000675
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00200
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000169
Gnomad4 OTH exome
AF:
0.000118
GnomAD4 genome
AF:
0.0000985
AC:
15
AN:
152284
Hom.:
0
Cov.:
33
AF XY:
0.000121
AC XY:
9
AN XY:
74466
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00290
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264
ExAC
AF:
0.000101
AC:
11
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

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

Submissions by phenotype

not provided Uncertain:1Benign:1
Jul 02, 2020
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 18, 2021
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1
Jun 20, 2017
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R2157C variant (also known as c.6469C>T), located in coding exon 45 of the CACNA1A gene, results from a C to T substitution at nucleotide position 6469. The arginine at codon 2157 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1
Sep 09, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

CACNA1A-related disorder Benign:1
Aug 19, 2021
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.39
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.43
.;T;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.54
FATHMM_MKL
Benign
0.27
N
LIST_S2
Uncertain
0.89
D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.38
D
MetaRNN
Benign
0.019
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.27
T
MutationAssessor
Uncertain
2.4
.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-3.6
.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Uncertain
0.43
Sift
Benign
0.17
.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Uncertain
0.035
D;D;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.30
MutPred
0.35
.;.;Loss of MoRF binding (P = 0.0574);Loss of MoRF binding (P = 0.0574);Loss of MoRF binding (P = 0.0574);.;.;Loss of MoRF binding (P = 0.0574);.;.;.;.;Loss of MoRF binding (P = 0.0574);.;.;.;.;.;
MVP
0.92
MPC
0.48
ClinPred
0.19
T
GERP RS
-1.4
Varity_R
0.26
gMVP
0.39

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: rs554393704; hg19: chr19-13320186; API