19-13209372-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_001127222.2(CACNA1A):c.6466C>G(p.Arg2156Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000358 in 1,395,592 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R2156H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 0.490

Publications

4 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:

ENSG00000300728 (HGNC:):

ENSG00000300728 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 19-13209372-G-C is Benign according to our data. Variant chr19-13209372-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 808464.

BS2

High AC in GnomAdExome4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.6466C>G	p.Arg2156Gly	missense_variant	Exon 45 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.6469C>G	p.Arg2157Gly	missense_variant	Exon 45 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.6466C>G	p.Arg2156Gly	missense_variant	Exon 45 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.6469C>G	p.Arg2157Gly	missense_variant	Exon 45 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.6484C>G	p.Arg2162Gly	missense_variant	Exon 46 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.6472C>G	p.Arg2158Gly	missense_variant	Exon 45 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.6469C>G	p.Arg2157Gly	missense_variant	Exon 45 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.6469C>G	p.Arg2157Gly	missense_variant	Exon 45 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.6433C>G	p.Arg2145Gly	missense_variant	Exon 44 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.6328C>G	p.Arg2110Gly	missense_variant	Exon 44 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.6469C>G	p.Arg2157Gly	missense_variant	Exon 45 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.6484C>G	p.Arg2162Gly	missense_variant	Exon 46 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.6475C>G	p.Arg2159Gly	missense_variant	Exon 46 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.6472C>G	p.Arg2158Gly	missense_variant	Exon 45 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.6469C>G	p.Arg2157Gly	missense_variant	Exon 45 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.6433C>G	p.Arg2145Gly	missense_variant	Exon 44 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.*732C>G		non_coding_transcript_exon_variant	Exon 43 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.*1645C>G		non_coding_transcript_exon_variant	Exon 45 of 47			ENSP00000519091.1
CACNA1A	ENST00000636768.2 link	n.*732C>G		3_prime_UTR_variant	Exon 43 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.*1645C>G		3_prime_UTR_variant	Exon 45 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

50246

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000370

AC:

AN:

1243426

Hom.:

Cov.:

AF XY:

0.0000333

AC XY:

AN XY:

600648

show subpopulations

African (AFR)

AF:

0.0000386

AC:

AN:

25890

American (AMR)

AF:

0.00

AC:

AN:

14824

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17316

East Asian (EAS)

AF:

0.00

AC:

AN:

30776

South Asian (SAS)

AF:

0.000169

AC:

AN:

53390

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42936

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4524

European-Non Finnish (NFE)

AF:

0.0000319

AC:

AN:

1003054

Other (OTH)

AF:

0.0000789

AC:

AN:

50716

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

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:

0.0000263

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.000131

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

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:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Dec 09, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in a patient with Familial Hemiplegic Migraine (FHM) and not in controls; however, further segregation analysis with family members was not completed (Grieco et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30167989, 32116539, 34426522)

Jul 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 12, 2021

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Benign:1

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EEG with focal epileptiform discharges

Benign:1

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant was found to be homozygous in the unaffected father of the patient.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.0

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

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.31

LIST_S2

Uncertain

0.88

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

M_CAP

Pathogenic

0.43

MetaRNN

Uncertain

0.52

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

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

0.0

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

PhyloP100

0.49

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.0

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

REVEL

Benign

0.0

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.022

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

Vest4

0.26

ClinPred

0.90

GERP RS

-1.4

Varity_R

0.64

gMVP

0.43

Mutation Taster

=35/65

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over