NM_001127222.2:c.3784G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_001127222.2(CACNA1A):c.3784G>A(p.Ala1262Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A1262A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.04

Publications

3 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.812

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.3784G>A	p.Ala1262Thr	missense_variant	Exon 22 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.3787G>A	p.Ala1263Thr	missense_variant	Exon 22 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.3784G>A	p.Ala1262Thr	missense_variant	Exon 22 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.3787G>A	p.Ala1263Thr	missense_variant	Exon 22 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.3796G>A	p.Ala1266Thr	missense_variant	Exon 22 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.3790G>A	p.Ala1264Thr	missense_variant	Exon 22 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.3787G>A	p.Ala1263Thr	missense_variant	Exon 22 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.3787G>A	p.Ala1263Thr	missense_variant	Exon 22 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.3787G>A	p.Ala1263Thr	missense_variant	Exon 22 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.3646G>A	p.Ala1216Thr	missense_variant	Exon 21 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.3787G>A	p.Ala1263Thr	missense_variant	Exon 22 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.3796G>A	p.Ala1266Thr	missense_variant	Exon 22 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.3787G>A	p.Ala1263Thr	missense_variant	Exon 22 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.3790G>A	p.Ala1264Thr	missense_variant	Exon 22 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.3787G>A	p.Ala1263Thr	missense_variant	Exon 22 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.3787G>A	p.Ala1263Thr	missense_variant	Exon 22 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.3787G>A		non_coding_transcript_exon_variant	Exon 22 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.3784G>A		non_coding_transcript_exon_variant	Exon 22 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000802

AC:

AN:

249258

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461668

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727124

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111838

Other (OTH)

AF:

0.00

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42

Uncertain:1

Mar 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1263 of the CACNA1A protein (p.Ala1263Thr). This variant is present in population databases (rs776503550, gnomAD 0.004%). This missense change has been observed in individual(s) with CACNA1A-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 566696). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1A protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Jun 29, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in an individual with ataxia, however, additional detailed clinical information was not provided (Coutelier et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27535533, 28444220) -

Developmental and epileptic encephalopathy, 42

Uncertain:1

Oct 14, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

.;D;T;.;.;.;.;.;.;T;.;.;.;T;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.98

D;D;D;D;D;D;D;D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.81

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.3

.;.;.;.;M;.;.;.;.;.;.;.;M;.;.

PhyloP100

6.0

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-4.0

.;D;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Pathogenic

0.79

Sift

Uncertain

0.016

.;D;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Uncertain

0.037

D;D;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.66

MutPred

0.47

.;.;Gain of glycosylation at A1263 (P = 0.0089);Gain of glycosylation at A1263 (P = 0.0089);Gain of glycosylation at A1263 (P = 0.0089);.;Gain of glycosylation at A1263 (P = 0.0089);.;.;Gain of glycosylation at A1263 (P = 0.0089);Gain of glycosylation at A1263 (P = 0.0089);.;Gain of glycosylation at A1263 (P = 0.0089);.;Gain of glycosylation at A1263 (P = 0.0089);

MVP

0.92

MPC

1.3

ClinPred

0.98

GERP RS

3.9

Varity_R

0.66

gMVP

0.85

Mutation Taster

=33/67

disease causing

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over