rs1052515747

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001127222.2(CACNA1A):c.7291G>C(p.Ala2431Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000307 in 1,303,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2431T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000031 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.86

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

CACNA1A links:

ENSG00000300728 (HGNC:):

ENSG00000300728 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2512473).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.7291G>C	p.Ala2431Pro	missense_variant	Exon 47 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.*503G>C		3_prime_UTR_variant	Exon 47 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.7291G>C	p.Ala2431Pro	missense_variant	Exon 47 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1 link	c.7309G>C	p.Ala2437Pro	missense_variant	Exon 48 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.7297G>C	p.Ala2433Pro	missense_variant	Exon 47 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.7294G>C	p.Ala2432Pro	missense_variant	Exon 47 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.7294G>C	p.Ala2432Pro	missense_variant	Exon 47 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.7258G>C	p.Ala2420Pro	missense_variant	Exon 46 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.7153G>C	p.Ala2385Pro	missense_variant	Exon 46 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636768.2 link	n.*1552G>C		non_coding_transcript_exon_variant	Exon 45 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.*2470G>C		non_coding_transcript_exon_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000638009.2 link	c.*503G>C		3_prime_UTR_variant	Exon 47 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000636389.1 link	c.*377G>C		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.*503G>C		3_prime_UTR_variant	Exon 48 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000635895.1 link	c.*503G>C		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000636768.2 link	n.*1552G>C		3_prime_UTR_variant	Exon 45 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.*2470G>C		3_prime_UTR_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000637276.1 link	c.*503G>C		downstream_gene_variant		5		ENSP00000489777.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

81706

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000307

AC:

AN:

1303348

Hom.:

Cov.:

AF XY:

0.00000156

AC XY:

AN XY:

643010

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25652

American (AMR)

AF:

0.00

AC:

AN:

26174

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22034

East Asian (EAS)

AF:

0.00

AC:

AN:

27284

South Asian (SAS)

AF:

0.00

AC:

AN:

72396

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36678

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4354

European-Non Finnish (NFE)

AF:

0.00000386

AC:

AN:

1035650

Other (OTH)

AF:

0.00

AC:

AN:

53126

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.48

DEOGEN2

Benign

0.027

.;.;T;.;.;T;.;T;.;.

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.68

T;T;T;T;T;T;.;T;T;T

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.25

T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.051

PhyloP100

2.9

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.3

.;N;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.31

Sift

Benign

0.18

.;T;.;.;.;.;.;.;.;.

Sift4G

Benign

0.22

T;T;.;T;.;.;.;.;.;.

Vest4

0.15

MutPred

0.24

.;Gain of glycosylation at A2431 (P = 0.0718);.;.;.;.;.;.;.;.;

MVP

0.79

MPC

0.93

ClinPred

0.49

GERP RS

1.5

Varity_R

0.099

gMVP

0.30

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over