NM_001127222.2:c.3310G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001127222.2(CACNA1A):c.3310G>A(p.Gly1104Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,606,038 control chromosomes in the GnomAD database, including 9,572 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.083 ( 662 hom., cov: 30)

Exomes 𝑓: 0.10 ( 8910 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O:1

Conservation

PhyloP100: 0.0340

Publications

28 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004124522).

BP6

Variant 19-13286746-C-T is Benign according to our data. Variant chr19-13286746-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 68428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127222.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1A	NM_001127222.2	MANE Select	c.3310G>A	p.Gly1104Ser	missense	Exon 20 of 47	NP_001120694.1
CACNA1A	NM_001127221.2	MANE Plus Clinical	c.3313G>A	p.Gly1105Ser	missense	Exon 20 of 47	NP_001120693.1
CACNA1A	NM_023035.3		c.3322G>A	p.Gly1108Ser	missense	Exon 20 of 48	NP_075461.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.3310G>A	p.Gly1104Ser	missense	Exon 20 of 47	ENSP00000353362.5
CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.3313G>A	p.Gly1105Ser	missense	Exon 20 of 47	ENSP00000489913.1
CACNA1A	ENST00000638029.1	TSL:5	c.3322G>A	p.Gly1108Ser	missense	Exon 20 of 48	ENSP00000489829.1

Frequencies

GnomAD3 genomes

AF:

0.0828

AC:

12562

AN:

151726

Hom.:

665

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0315

Gnomad AMI

AF:

0.0857

Gnomad AMR

AF:

0.103

Gnomad ASJ

AF:

0.111

Gnomad EAS

AF:

0.0740

Gnomad SAS

AF:

0.228

Gnomad FIN

AF:

0.103

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0951

Gnomad OTH

AF:

0.0820

GnomAD2 exomes

AF:

0.109

AC:

25976

AN:

238848

AF XY:

0.117

show subpopulations

Gnomad AFR exome

AF:

0.0294

Gnomad AMR exome

AF:

0.0915

Gnomad ASJ exome

AF:

0.105

Gnomad EAS exome

AF:

0.0852

Gnomad FIN exome

AF:

0.0954

Gnomad NFE exome

AF:

0.0964

Gnomad OTH exome

AF:

0.0963

GnomAD4 exome

AF:

0.103

AC:

149879

AN:

1454194

Hom.:

8910

Cov.:

AF XY:

0.108

AC XY:

78130

AN XY:

722788

show subpopulations

African (AFR)

AF:

0.0300

AC:

1000

AN:

33376

American (AMR)

AF:

0.0890

AC:

3944

AN:

44296

Ashkenazi Jewish (ASJ)

AF:

0.108

AC:

2783

AN:

25860

East Asian (EAS)

AF:

0.0572

AC:

2261

AN:

39538

South Asian (SAS)

AF:

0.236

AC:

20260

AN:

85880

European-Finnish (FIN)

AF:

0.0890

AC:

4537

AN:

50978

Middle Eastern (MID)

AF:

0.110

AC:

634

AN:

5744

European-Non Finnish (NFE)

AF:

0.0977

AC:

108292

AN:

1108408

Other (OTH)

AF:

0.103

AC:

6168

AN:

60114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

7381

14761

22142

29522

36903

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4084

8168

12252

16336

20420

<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:

0.0826

AC:

12544

AN:

151844

Hom.:

662

Cov.:

AF XY:

0.0862

AC XY:

6394

AN XY:

74204

show subpopulations

African (AFR)

AF:

0.0315

AC:

1303

AN:

41430

American (AMR)

AF:

0.103

AC:

1564

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.111

AC:

385

AN:

3470

East Asian (EAS)

AF:

0.0735

AC:

378

AN:

5140

South Asian (SAS)

AF:

0.228

AC:

1091

AN:

4794

European-Finnish (FIN)

AF:

0.103

AC:

1085

AN:

10530

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0951

AC:

6460

AN:

67910

Other (OTH)

AF:

0.0802

AC:

169

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

557

1115

1672

2230

2787

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

162

324

486

648

810

<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:

0.0938

Hom.:

1377

Bravo

AF:

0.0774

TwinsUK

AF:

0.0974

AC:

361

ALSPAC

AF:

0.0960

AC:

370

ESP6500AA

AF:

0.0331

AC:

128

ESP6500EA

AF:

0.0930

AC:

765

ExAC

AF:

0.107

AC:

12832

Asia WGS

AF:

0.116

AC:

408

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (9)

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 (1)

Inborn genetic diseases (1)

not provided (2)

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.019

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0041

MetaSVM

Benign

-0.50

MutationAssessor

Benign

1.1

PhyloP100

0.034

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.0

REVEL

Benign

0.17

Sift

Benign

0.19

Sift4G

Benign

0.19

Vest4

0.050

MPC

0.086

ClinPred

0.012

GERP RS

-0.31

Varity_R

0.048

gMVP

0.44

Mutation Taster

=96/4

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over