NM_001127222.2:c.2692G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001127222.2(CACNA1A):​c.2692G>A​(p.Gly898Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,592,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G898R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

2
5
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 4.75

Publications

1 publications found
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]
CACNA1A Gene-Disease associations (from GenCC):
  • episodic ataxia type 2
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • undetermined early-onset epileptic encephalopathy
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
  • developmental and epileptic encephalopathy, 42
    Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • migraine, familial hemiplegic, 1
    Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
  • spinocerebellar ataxia type 6
    Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
  • benign paroxysmal torticollis of infancy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • familial or sporadic hemiplegic migraine
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Lennox-Gastaut syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.21210161).
BP6
Variant 19-13298941-C-T is Benign according to our data. Variant chr19-13298941-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 572781.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1ANM_001127222.2 linkc.2692G>A p.Gly898Ser missense_variant Exon 19 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.2692G>A p.Gly898Ser missense_variant Exon 19 of 47 1 NM_001127222.2 ENSP00000353362.5 O00555-8
CACNA1AENST00000638029.1 linkc.2704G>A p.Gly902Ser missense_variant Exon 19 of 48 5 ENSP00000489829.1 A0A087WW63
CACNA1AENST00000573710.7 linkc.2698G>A p.Gly900Ser missense_variant Exon 19 of 47 5 ENSP00000460092.3 A0A1C7CYY9
CACNA1AENST00000635727.1 linkc.2695G>A p.Gly899Ser missense_variant Exon 19 of 47 5 ENSP00000490001.1 A0A1B0GU81
CACNA1AENST00000637769.1 linkc.2695G>A p.Gly899Ser missense_variant Exon 19 of 47 1 ENSP00000489778.1 A0A1B0GTN7
CACNA1AENST00000636012.1 linkc.2695G>A p.Gly899Ser missense_variant Exon 19 of 46 5 ENSP00000490223.1 A0A1B0GUS3
CACNA1AENST00000637736.1 linkc.2554G>A p.Gly852Ser missense_variant Exon 18 of 46 5 ENSP00000489861.1 A0A1B0GTW2
CACNA1AENST00000636389.1 linkc.2695G>A p.Gly899Ser missense_variant Exon 19 of 47 5 ENSP00000489992.1 A0A1B0GU74
CACNA1AENST00000637432.1 linkc.2704G>A p.Gly902Ser missense_variant Exon 19 of 48 5 ENSP00000490617.1 O00555-2
CACNA1AENST00000636549.1 linkc.2695G>A p.Gly899Ser missense_variant Exon 19 of 48 5 ENSP00000490578.1 B5TYJ1
CACNA1AENST00000637927.1 linkc.2698G>A p.Gly900Ser missense_variant Exon 19 of 47 5 ENSP00000489715.1 A0A1B0GTI4
CACNA1AENST00000635895.1 linkc.2695G>A p.Gly899Ser missense_variant Exon 19 of 47 5 ENSP00000490323.1 A0A384DVW2
CACNA1AENST00000638009.2 linkc.2695G>A p.Gly899Ser missense_variant Exon 19 of 47 1 ENSP00000489913.1 O00555-3
CACNA1AENST00000637276.1 linkc.2695G>A p.Gly899Ser missense_variant Exon 19 of 46 5 ENSP00000489777.1 O00555-5
CACNA1AENST00000636768.2 linkn.2695G>A non_coding_transcript_exon_variant Exon 19 of 45 5 ENSP00000490190.2 A0A1B0GUP3
CACNA1AENST00000713789.1 linkn.2692G>A non_coding_transcript_exon_variant Exon 19 of 47 ENSP00000519091.1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152186
Hom.:
0
Cov.:
32
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000372
AC:
8
AN:
214956
AF XY:
0.0000418
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000121
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000410
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000118
AC:
170
AN:
1440550
Hom.:
0
Cov.:
32
AF XY:
0.000120
AC XY:
86
AN XY:
716688
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33310
American (AMR)
AF:
0.0000908
AC:
4
AN:
44038
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25934
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39418
South Asian (SAS)
AF:
0.0000117
AC:
1
AN:
85268
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
38050
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5596
European-Non Finnish (NFE)
AF:
0.000140
AC:
155
AN:
1109018
Other (OTH)
AF:
0.000167
AC:
10
AN:
59918
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.488
Heterozygous variant carriers
0
12
24
36
48
60
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
10
20
30
40
50
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152186
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74340
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41446
American (AMR)
AF:
0.00
AC:
0
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4838
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
0.0000735
AC:
5
AN:
68024
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000583
Hom.:
0
Bravo
AF:
0.0000642
ExAC
AF:
0.00000852
AC:
1

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:5
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Migraine, familial hemiplegic, 1 Uncertain:1
Jul 18, 2022
Institute of Human Genetics, University of Leipzig Medical Center
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

_x000D_ Criteria applied: PP3, BS1 -

Intellectual disability Uncertain:1
Apr 29, 2020
Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
Jul 09, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: CACNA1A c.2695G>A (p.Gly899Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was detected at a frequency of 0.00011 in 1592736 control chromosomes, suggesting the variant could be benign. To our knowledge, no occurrence of c.2695G>A in individuals affected with Epileptic Encephalopathy, Early Infantile, 42 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 572781). Based on the evidence outlined above, the variant was classified as likely benign. -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1
Oct 06, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Inborn genetic diseases Benign:1
Jun 24, 2019
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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. -

not provided Benign:1
Jul 29, 2020
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

CACNA1A-related disorder Benign:1
Sep 05, 2023
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
Benign
0.084
BayesDel_addAF
Benign
-0.021
T
BayesDel_noAF
Uncertain
-0.040
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Benign
0.0083
.;.;T;.;.;.;.;.;.;T;.;.;.;T;.
Eigen
Benign
-0.50
Eigen_PC
Benign
-0.59
FATHMM_MKL
Benign
0.71
D
LIST_S2
Uncertain
0.87
D;D;D;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.93
D
MetaRNN
Benign
0.21
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.11
D
MutationAssessor
Benign
1.5
.;.;.;.;L;.;.;.;.;.;.;.;L;.;.
PhyloP100
4.8
PrimateAI
Pathogenic
0.84
D
PROVEAN
Benign
-0.28
.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL
Uncertain
0.32
Sift
Benign
0.41
.;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G
Benign
0.57
T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
0.11
MutPred
0.16
.;.;Gain of phosphorylation at G899 (P = 0.0057);Gain of phosphorylation at G899 (P = 0.0057);Gain of phosphorylation at G899 (P = 0.0057);.;Gain of phosphorylation at G899 (P = 0.0057);.;.;Gain of phosphorylation at G899 (P = 0.0057);Gain of phosphorylation at G899 (P = 0.0057);.;Gain of phosphorylation at G899 (P = 0.0057);.;Gain of phosphorylation at G899 (P = 0.0057);
MVP
0.94
MPC
1.1
ClinPred
0.13
T
GERP RS
3.0
Varity_R
0.071
gMVP
0.52
Mutation Taster
=86/14
polymorphism

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

Other links and lift over

dbSNP: rs751726770; hg19: chr19-13409755; API