19-13298726-C-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_001127222.2(CACNA1A):​c.2907G>A​(p.Pro969Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000934 in 1,498,900 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -4.76

Publications

0 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 -17 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.75).
BP6
Variant 19-13298726-C-T is Benign according to our data. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13298726-C-T is described in CliVar as Likely_benign. Clinvar id is 476245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-4.76 with no splicing effect.
BS2
High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CACNA1ANM_001127222.2 linkc.2907G>A p.Pro969Pro synonymous_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.2907G>A p.Pro969Pro synonymous_variant Exon 19 of 47 1 NM_001127222.2 ENSP00000353362.5 O00555-8
CACNA1AENST00000638029.1 linkc.2919G>A p.Pro973Pro synonymous_variant Exon 19 of 48 5 ENSP00000489829.1 A0A087WW63
CACNA1AENST00000573710.7 linkc.2913G>A p.Pro971Pro synonymous_variant Exon 19 of 47 5 ENSP00000460092.3 A0A1C7CYY9
CACNA1AENST00000635727.1 linkc.2910G>A p.Pro970Pro synonymous_variant Exon 19 of 47 5 ENSP00000490001.1 A0A1B0GU81
CACNA1AENST00000637769.1 linkc.2910G>A p.Pro970Pro synonymous_variant Exon 19 of 47 1 ENSP00000489778.1 A0A1B0GTN7
CACNA1AENST00000636012.1 linkc.2910G>A p.Pro970Pro synonymous_variant Exon 19 of 46 5 ENSP00000490223.1 A0A1B0GUS3
CACNA1AENST00000637736.1 linkc.2769G>A p.Pro923Pro synonymous_variant Exon 18 of 46 5 ENSP00000489861.1 A0A1B0GTW2
CACNA1AENST00000636389.1 linkc.2910G>A p.Pro970Pro synonymous_variant Exon 19 of 47 5 ENSP00000489992.1 A0A1B0GU74
CACNA1AENST00000637432.1 linkc.2919G>A p.Pro973Pro synonymous_variant Exon 19 of 48 5 ENSP00000490617.1 O00555-2
CACNA1AENST00000636549.1 linkc.2910G>A p.Pro970Pro synonymous_variant Exon 19 of 48 5 ENSP00000490578.1 B5TYJ1
CACNA1AENST00000637927.1 linkc.2913G>A p.Pro971Pro synonymous_variant Exon 19 of 47 5 ENSP00000489715.1 A0A1B0GTI4
CACNA1AENST00000635895.1 linkc.2910G>A p.Pro970Pro synonymous_variant Exon 19 of 47 5 ENSP00000490323.1 A0A384DVW2
CACNA1AENST00000638009.2 linkc.2910G>A p.Pro970Pro synonymous_variant Exon 19 of 47 1 ENSP00000489913.1 O00555-3
CACNA1AENST00000637276.1 linkc.2910G>A p.Pro970Pro synonymous_variant Exon 19 of 46 5 ENSP00000489777.1 O00555-5
CACNA1AENST00000636768.2 linkn.2910G>A non_coding_transcript_exon_variant Exon 19 of 45 5 ENSP00000490190.2 A0A1B0GUP3
CACNA1AENST00000713789.1 linkn.2907G>A non_coding_transcript_exon_variant Exon 19 of 47 ENSP00000519091.1

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
151994
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000328
Gnomad ASJ
AF:
0.00375
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:
0.000479
GnomAD2 exomes
AF:
0.000340
AC:
33
AN:
97186
AF XY:
0.000366
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000278
Gnomad ASJ exome
AF:
0.00373
Gnomad EAS exome
AF:
0.000197
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000566
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000869
AC:
117
AN:
1346906
Hom.:
0
Cov.:
32
AF XY:
0.0000903
AC XY:
60
AN XY:
664254
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
26980
American (AMR)
AF:
0.000170
AC:
5
AN:
29358
Ashkenazi Jewish (ASJ)
AF:
0.00336
AC:
79
AN:
23520
East Asian (EAS)
AF:
0.0000656
AC:
2
AN:
30470
South Asian (SAS)
AF:
0.00
AC:
0
AN:
74282
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
40768
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4886
European-Non Finnish (NFE)
AF:
0.0000179
AC:
19
AN:
1060926
Other (OTH)
AF:
0.000215
AC:
12
AN:
55716
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.513
Heterozygous variant carriers
0
8
16
23
31
39
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000151
AC:
23
AN:
151994
Hom.:
0
Cov.:
32
AF XY:
0.000216
AC XY:
16
AN XY:
74246
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41424
American (AMR)
AF:
0.000328
AC:
5
AN:
15260
Ashkenazi Jewish (ASJ)
AF:
0.00375
AC:
13
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5170
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10546
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
312
European-Non Finnish (NFE)
AF:
0.0000588
AC:
4
AN:
67980
Other (OTH)
AF:
0.000479
AC:
1
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000659
Hom.:
0
Bravo
AF:
0.000128

ClinVar

Significance: Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Jun 12, 2021
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

CACNA1A: BP4, BP7 -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1
Dec 19, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Inborn genetic diseases Benign:1
Oct 23, 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.75
CADD
Benign
2.9
DANN
Benign
0.93
PhyloP100
-4.8
Mutation Taster
=99/1
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: rs772557121; hg19: chr19-13409540; API