rs369742607

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001127222.2(CACNA1A):c.3544G>A(p.Val1182Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,364,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1182A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000088 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 0.908

Publications

1 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.067641616).

BP6

Variant 19-13286512-C-T is Benign according to our data. Variant chr19-13286512-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 476255.

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.3544G>A	p.Val1182Ile	missense_variant	Exon 20 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.3547G>A	p.Val1183Ile	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.3544G>A	p.Val1182Ile	missense_variant	Exon 20 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.3547G>A	p.Val1183Ile	missense_variant	Exon 20 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.3556G>A	p.Val1186Ile	missense_variant	Exon 20 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.3550G>A	p.Val1184Ile	missense_variant	Exon 20 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.3547G>A	p.Val1183Ile	missense_variant	Exon 20 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.3547G>A	p.Val1183Ile	missense_variant	Exon 20 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.3547G>A	p.Val1183Ile	missense_variant	Exon 20 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.3406G>A	p.Val1136Ile	missense_variant	Exon 19 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.3547G>A	p.Val1183Ile	missense_variant	Exon 20 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.3556G>A	p.Val1186Ile	missense_variant	Exon 20 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.3547G>A	p.Val1183Ile	missense_variant	Exon 20 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.3550G>A	p.Val1184Ile	missense_variant	Exon 20 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.3547G>A	p.Val1183Ile	missense_variant	Exon 20 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.3547G>A	p.Val1183Ile	missense_variant	Exon 20 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.3547G>A		non_coding_transcript_exon_variant	Exon 20 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.3544G>A		non_coding_transcript_exon_variant	Exon 20 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

AF:

0.0000879

AC:

AN:

147826

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000675

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000406

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000134

Gnomad OTH

AF:

0.000490

GnomAD2 exomes

AF:

0.000171

AC:

AN:

169696

AF XY:

0.000200

show subpopulations

Gnomad AFR exome

AF:

0.0000719

Gnomad AMR exome

AF:

0.000244

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000470

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000181

Gnomad OTH exome

AF:

0.000261

GnomAD4 exome

AF:

0.000118

AC:

143

AN:

1216870

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

602294

show subpopulations

African (AFR)

AF:

0.0000731

AC:

AN:

27360

American (AMR)

AF:

0.000174

AC:

AN:

28746

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18932

East Asian (EAS)

AF:

0.000212

AC:

AN:

37746

South Asian (SAS)

AF:

0.0000153

AC:

AN:

65470

European-Finnish (FIN)

AF:

0.0000817

AC:

AN:

48956

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4992

European-Non Finnish (NFE)

AF:

0.000121

AC:

113

AN:

933548

Other (OTH)

AF:

0.000196

AC:

AN:

51120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.0000879

AC:

AN:

147826

Hom.:

Cov.:

AF XY:

0.0000556

AC XY:

AN XY:

71926

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

39944

American (AMR)

AF:

0.0000675

AC:

AN:

14812

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3446

East Asian (EAS)

AF:

0.000406

AC:

AN:

4922

South Asian (SAS)

AF:

0.00

AC:

AN:

4552

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000134

AC:

AN:

67274

Other (OTH)

AF:

0.000490

AC:

AN:

2040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.0000760

Hom.:

Bravo

AF:

0.000121

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.000152

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

May 09, 2018

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 07, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 05, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Jun 20, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CACNA1A c.3547G>A (p.Val1183Ile) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be tolerated. The variant allele was found at a frequency of 0.00017 in 169696 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CACNA1A causing Epileptic Encephalopathy, Early Infantile, 42, allowing no conclusion about variant significance. c.3547G>A has been observed in an individual and their similarly affected sister with myoclonic astatic epilepsy, attention deficit hyperactivity disorder (ADHD), and intellectual disability; however, the variant was also found in their unaffected mother (example: Poliquin_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33961861). ClinVar contains an entry for this variant (Variation ID: 476255). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Sep 27, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0089

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

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.70

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

M_CAP

Benign

0.0091

MetaRNN

Benign

0.068

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

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

PhyloP100

0.91

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.41

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

REVEL

Benign

0.049

Sift

Benign

0.22

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

Sift4G

Benign

0.30

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

Vest4

0.091

MVP

0.37

MPC

0.013

ClinPred

0.019

GERP RS

4.3

Varity_R

0.036

gMVP

0.20

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

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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