rs764816582

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_001127222.2(CACNA1A):​c.2256C>T​(p.Ser752Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,260 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 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 synonymous

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.78
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.64).
BP6
Variant 19-13300573-G-A is Benign according to our data. Variant chr19-13300573-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 589166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-3.78 with no splicing effect.
BS2
High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1ANM_001127222.2 linkuse as main transcriptc.2256C>T p.Ser752Ser synonymous_variant 18/47 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.2256C>T p.Ser752Ser synonymous_variant 18/471 NM_001127222.2 ENSP00000353362.5 O00555-8
CACNA1AENST00000638029.1 linkuse as main transcriptc.2268C>T p.Ser756Ser synonymous_variant 18/485 ENSP00000489829.1 A0A087WW63
CACNA1AENST00000573710.7 linkuse as main transcriptc.2262C>T p.Ser754Ser synonymous_variant 18/475 ENSP00000460092.3 A0A1C7CYY9
CACNA1AENST00000635727.1 linkuse as main transcriptc.2259C>T p.Ser753Ser synonymous_variant 18/475 ENSP00000490001.1 A0A1B0GU81
CACNA1AENST00000637769.1 linkuse as main transcriptc.2259C>T p.Ser753Ser synonymous_variant 18/471 ENSP00000489778.1 A0A1B0GTN7
CACNA1AENST00000636012.1 linkuse as main transcriptc.2259C>T p.Ser753Ser synonymous_variant 18/465 ENSP00000490223.1 A0A1B0GUS3
CACNA1AENST00000637736.1 linkuse as main transcriptc.2118C>T p.Ser706Ser synonymous_variant 17/465 ENSP00000489861.1 A0A1B0GTW2
CACNA1AENST00000636389.1 linkuse as main transcriptc.2259C>T p.Ser753Ser synonymous_variant 18/475 ENSP00000489992.1 A0A1B0GU74
CACNA1AENST00000637432.1 linkuse as main transcriptc.2268C>T p.Ser756Ser synonymous_variant 18/485 ENSP00000490617.1 O00555-2
CACNA1AENST00000636549.1 linkuse as main transcriptc.2259C>T p.Ser753Ser synonymous_variant 18/485 ENSP00000490578.1 B5TYJ1
CACNA1AENST00000637927.1 linkuse as main transcriptc.2262C>T p.Ser754Ser synonymous_variant 18/475 ENSP00000489715.1 A0A1B0GTI4
CACNA1AENST00000635895.1 linkuse as main transcriptc.2259C>T p.Ser753Ser synonymous_variant 18/475 ENSP00000490323.1 A0A384DVW2
CACNA1AENST00000638009.2 linkuse as main transcriptc.2259C>T p.Ser753Ser synonymous_variant 18/471 ENSP00000489913.1 O00555-3
CACNA1AENST00000637276.1 linkuse as main transcriptc.2259C>T p.Ser753Ser synonymous_variant 18/465 ENSP00000489777.1 O00555-5

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152102
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
249304
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135250
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:
0.0000265
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000171
AC:
25
AN:
1461158
Hom.:
0
Cov.:
30
AF XY:
0.00000963
AC XY:
7
AN XY:
726922
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000189
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152102
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74300
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000480
Hom.:
0

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 08, 2019- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 31, 2017This 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
-0.64
CADD
Benign
4.3
DANN
Benign
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs764816582; hg19: chr19-13411387; API