chr19-13262789-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_001127222.2(CACNA1A):c.4034G>A(p.Arg1345Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,366 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1345L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 7.88

Publications

23 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: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_001127222.2

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-13262789-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1803511.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

PP5

Variant 19-13262789-C-T is Pathogenic according to our data. Variant chr19-13262789-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.4034G>A	p.Arg1345Gln	missense_variant	Exon 25 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.4037G>A	p.Arg1346Gln	missense_variant	Exon 25 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.4034G>A	p.Arg1345Gln	missense_variant	Exon 25 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.4037G>A	p.Arg1346Gln	missense_variant	Exon 25 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.4046G>A	p.Arg1349Gln	missense_variant	Exon 25 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.4040G>A	p.Arg1347Gln	missense_variant	Exon 25 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.4037G>A	p.Arg1346Gln	missense_variant	Exon 25 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.4037G>A	p.Arg1346Gln	missense_variant	Exon 25 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.4037G>A	p.Arg1346Gln	missense_variant	Exon 25 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.3896G>A	p.Arg1299Gln	missense_variant	Exon 24 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.4037G>A	p.Arg1346Gln	missense_variant	Exon 25 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.4046G>A	p.Arg1349Gln	missense_variant	Exon 25 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.4037G>A	p.Arg1346Gln	missense_variant	Exon 25 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.4040G>A	p.Arg1347Gln	missense_variant	Exon 25 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.4037G>A	p.Arg1346Gln	missense_variant	Exon 25 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.4037G>A	p.Arg1346Gln	missense_variant	Exon 25 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.4037G>A		non_coding_transcript_exon_variant	Exon 25 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.4034G>A		non_coding_transcript_exon_variant	Exon 25 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461366

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726936

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86180

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111686

Other (OTH)

AF:

0.00

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Jan 12, 2022

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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: 27435762, 15032980, 29482223, 33790770) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 22, 2022

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant segregates with hemiplegic migraine with progressive cerebellar ataxia in at least one family and has also been seen in at least one de novo case. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging. -

Migraine, familial hemiplegic, 1

Pathogenic:1Other:1

Nov 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

UniProtKB/Swiss-Prot

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

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

Pathogenic:1

Oct 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1346 of the CACNA1A protein (p.Arg1346Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with developmental and epileptic encephalopathy (PMID: 19811514). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 8513). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CACNA1A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

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

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PP2+PS4+PM6+PP1_Moderate+PP3_Strong+PP4 -

Developmental and epileptic encephalopathy, 42

Pathogenic:1

Jun 01, 2022

Solve-RD Consortium

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.49

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

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.98

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.7

.;.;.;.;H;.;.;.;.;.;.;.;H;.;.

PhyloP100

7.9

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-4.0

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

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Vest4

0.97

MutPred

0.89

.;.;Loss of MoRF binding (P = 0.0298);Loss of MoRF binding (P = 0.0298);Loss of MoRF binding (P = 0.0298);.;Loss of MoRF binding (P = 0.0298);.;.;Loss of MoRF binding (P = 0.0298);Loss of MoRF binding (P = 0.0298);.;Loss of MoRF binding (P = 0.0298);.;Loss of MoRF binding (P = 0.0298);

MVP

1.0

MPC

2.4

ClinPred

1.0

GERP RS

5.4

Varity_R

0.80

gMVP

1.0

Mutation Taster

=0/100

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over