19-13286566-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_001127222.2(CACNA1A):c.3490G>A(p.Asp1164Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000907 in 1,544,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000072 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.13

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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22467071).

BP6

Variant 19-13286566-C-T is Benign according to our data. Variant chr19-13286566-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 476254.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.3490G>A	p.Asp1164Asn	missense_variant	Exon 20 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.3493G>A	p.Asp1165Asn	missense_variant	Exon 20 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.3490G>A	p.Asp1164Asn	missense_variant	Exon 20 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.3493G>A	p.Asp1165Asn	missense_variant	Exon 20 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.3502G>A	p.Asp1168Asn	missense_variant	Exon 20 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.3496G>A	p.Asp1166Asn	missense_variant	Exon 20 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.3493G>A	p.Asp1165Asn	missense_variant	Exon 20 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.3493G>A	p.Asp1165Asn	missense_variant	Exon 20 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.3493G>A	p.Asp1165Asn	missense_variant	Exon 20 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.3352G>A	p.Asp1118Asn	missense_variant	Exon 19 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.3493G>A	p.Asp1165Asn	missense_variant	Exon 20 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.3502G>A	p.Asp1168Asn	missense_variant	Exon 20 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.3493G>A	p.Asp1165Asn	missense_variant	Exon 20 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.3496G>A	p.Asp1166Asn	missense_variant	Exon 20 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.3493G>A	p.Asp1165Asn	missense_variant	Exon 20 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.3493G>A	p.Asp1165Asn	missense_variant	Exon 20 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.3493G>A		non_coding_transcript_exon_variant	Exon 20 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.3490G>A		non_coding_transcript_exon_variant	Exon 20 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

AF:

0.0000272

AC:

AN:

146956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000764

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:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000262

AC:

AN:

191024

AF XY:

0.0000393

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000398

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000335

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000716

AC:

AN:

1397168

Hom.:

Cov.:

AF XY:

0.00000725

AC XY:

AN XY:

689612

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31020

American (AMR)

AF:

0.0000294

AC:

AN:

34058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21404

East Asian (EAS)

AF:

0.00

AC:

AN:

39200

South Asian (SAS)

AF:

0.0000269

AC:

AN:

74324

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50744

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5406

European-Non Finnish (NFE)

AF:

0.00000554

AC:

AN:

1083408

Other (OTH)

AF:

0.0000174

AC:

AN:

57604

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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

AF:

0.0000272

AC:

AN:

146956

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

71230

show subpopulations

African (AFR)

AF:

0.0000764

AC:

AN:

39270

American (AMR)

AF:

0.00

AC:

AN:

14524

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

4958

South Asian (SAS)

AF:

0.00

AC:

AN:

4648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

302

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67300

Other (OTH)

AF:

0.00

AC:

AN:

2004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000658

Hom.:

ExAC

AF:

0.0000250

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Nov 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.019

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

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.072

MetaRNN

Benign

0.22

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

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.0

.;.;.;.;L;.;.;.;.;.;.;.;L;.;.

PhyloP100

6.1

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.9

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

REVEL

Benign

0.14

Sift

Benign

0.32

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

Sift4G

Benign

0.14

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

Vest4

0.34

MVP

0.60

MPC

0.082

ClinPred

0.72

GERP RS

5.3

Varity_R

0.17

gMVP

0.38

Mutation Taster

=72/28

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over