NM_001127222.2:c.2192A>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001127222.2(CACNA1A):c.2192A>C(p.Glu731Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0112 in 1,613,542 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 21 hom., cov: 32)

Exomes 𝑓: 0.011 ( 111 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 5.03

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in the CACNA1A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 137 curated pathogenic missense variants (we use a threshold of 10). The gene has 132 curated benign missense variants. Gene score misZ: 5.7845 (above the threshold of 3.09). Trascript score misZ: 3.9354 (above the threshold of 3.09). GenCC associations: The gene is linked to benign paroxysmal torticollis of infancy, developmental and epileptic encephalopathy, 42, undetermined early-onset epileptic encephalopathy, episodic ataxia type 2, familial or sporadic hemiplegic migraine, spinocerebellar ataxia type 6, Lennox-Gastaut syndrome, migraine, familial hemiplegic, 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.009210616).

BP6

Variant 19-13300637-T-G is Benign according to our data. Variant chr19-13300637-T-G is described in ClinVar as [Benign]. Clinvar id is 128547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13300637-T-G is described in Lovd as [Benign]. Variant chr19-13300637-T-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0101 (1541/152282) while in subpopulation NFE AF= 0.0154 (1050/68018). AF 95% confidence interval is 0.0147. There are 21 homozygotes in gnomad4. There are 763 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1541 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.2192A>C	p.Glu731Ala	missense_variant	Exon 18 of 47	ENST00000360228.11	NP_001120694.1	O00555-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1A	ENST00000360228.11 link	c.2192A>C	p.Glu731Ala	missense_variant	Exon 18 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.2204A>C	p.Glu735Ala	missense_variant	Exon 18 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.2198A>C	p.Glu733Ala	missense_variant	Exon 18 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.2195A>C	p.Glu732Ala	missense_variant	Exon 18 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.2195A>C	p.Glu732Ala	missense_variant	Exon 18 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.2195A>C	p.Glu732Ala	missense_variant	Exon 18 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.2054A>C	p.Glu685Ala	missense_variant	Exon 17 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 link	c.2195A>C	p.Glu732Ala	missense_variant	Exon 18 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.2204A>C	p.Glu735Ala	missense_variant	Exon 18 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 link	c.2195A>C	p.Glu732Ala	missense_variant	Exon 18 of 48	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.2198A>C	p.Glu733Ala	missense_variant	Exon 18 of 47	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 link	c.2195A>C	p.Glu732Ala	missense_variant	Exon 18 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.2195A>C	p.Glu732Ala	missense_variant	Exon 18 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.2195A>C	p.Glu732Ala	missense_variant	Exon 18 of 46	5		ENSP00000489777.1	O00555-5

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1542

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00220

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00504

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.0248

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0154

Gnomad OTH

AF:

0.00716

GnomAD3 exomes

AF:

0.0105

AC:

2609

AN:

249304

Hom.:

AF XY:

0.0104

AC XY:

1413

AN XY:

135252

show subpopulations

Gnomad AFR exome

AF:

0.00207

Gnomad AMR exome

AF:

0.00469

Gnomad ASJ exome

AF:

0.00606

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00559

Gnomad FIN exome

AF:

0.0237

Gnomad NFE exome

AF:

0.0141

Gnomad OTH exome

AF:

0.0132

GnomAD4 exome

AF:

0.0113

AC:

16489

AN:

1461260

Hom.:

111

Cov.:

AF XY:

0.0113

AC XY:

8215

AN XY:

726972

show subpopulations

Gnomad4 AFR exome

AF:

0.00200

Gnomad4 AMR exome

AF:

0.00523

Gnomad4 ASJ exome

AF:

0.00509

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.00572

Gnomad4 FIN exome

AF:

0.0222

Gnomad4 NFE exome

AF:

0.0124

Gnomad4 OTH exome

AF:

0.00936

GnomAD4 genome

AF:

0.0101

AC:

1541

AN:

152282

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

763

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00219

Gnomad4 AMR

AF:

0.00504

Gnomad4 ASJ

AF:

0.00518

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.0248

Gnomad4 NFE

AF:

0.0154

Gnomad4 OTH

AF:

0.00709

Alfa

AF:

0.0126

Hom.:

Bravo

AF:

0.00815

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.00199

AC:

ESP6500EA

AF:

0.0134

AC:

112

ExAC

AF:

0.0101

AC:

1223

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0130

EpiControl

AF:

0.0140

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 24, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Jun 02, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1A: PP2, BS1, BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Feb 24, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Benign

0.94

DEOGEN2

Pathogenic

0.83

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

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

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

MetaRNN

Benign

0.0092

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

MetaSVM

Uncertain

0.51

MutationAssessor

Benign

1.5

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

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.5

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

REVEL

Uncertain

0.47

Sift

Benign

0.035

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

Sift4G

Benign

0.091

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

Vest4

0.33

MPC

2.3

ClinPred

0.037

GERP RS

4.9

Varity_R

0.34

gMVP

0.89

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over