19-13231774-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_001127222.2(CACNA1A):c.5336G>A(p.Arg1779Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,613,722 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). Synonymous variant affecting the same amino acid position (i.e. R1779R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.02

Publications

0 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: Likely_benign. The variant received -4 ACMG points.

PM1

In a repeat IV (size 263) in uniprot entity CAC1A_HUMAN there are 39 pathogenic changes around while only 10 benign (80%) in NM_001127222.2

BP4

Computational evidence support a benign effect (MetaRNN=0.11609897).

BS2

High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.5336G>A	p.Arg1779Gln	missense_variant	Exon 35 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.5336G>A	p.Arg1779Gln	missense_variant	Exon 35 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.5354G>A	p.Arg1785Gln	missense_variant	Exon 36 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.5342G>A	p.Arg1781Gln	missense_variant	Exon 35 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.5339G>A	p.Arg1780Gln	missense_variant	Exon 35 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.5339G>A	p.Arg1780Gln	missense_variant	Exon 35 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.5339G>A	p.Arg1780Gln	missense_variant	Exon 35 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.5198G>A	p.Arg1733Gln	missense_variant	Exon 34 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 link	c.5339G>A	p.Arg1780Gln	missense_variant	Exon 35 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.5354G>A	p.Arg1785Gln	missense_variant	Exon 36 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 link	c.5345G>A	p.Arg1782Gln	missense_variant	Exon 36 of 48	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.5342G>A	p.Arg1781Gln	missense_variant	Exon 35 of 47	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 link	c.5339G>A	p.Arg1780Gln	missense_variant	Exon 35 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.5339G>A	p.Arg1780Gln	missense_variant	Exon 35 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.5339G>A	p.Arg1780Gln	missense_variant	Exon 35 of 46	5		ENSP00000489777.1	O00555-5
CACNA1A	ENST00000636768.2 link	n.5339G>A		non_coding_transcript_exon_variant	Exon 35 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.*517G>A		non_coding_transcript_exon_variant	Exon 36 of 47			ENSP00000519091.1
CACNA1A	ENST00000713789.1 link	n.*517G>A		3_prime_UTR_variant	Exon 36 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000803

AC:

AN:

249216

AF XY:

0.0000148

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:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461556

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727052

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1111768

Other (OTH)

AF:

0.0000166

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Aug 26, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5339G>A (p.R1780Q) alteration is located in exon 35 (coding exon 35) of the CACNA1A gene. This alteration results from a G to A substitution at nucleotide position 5339, causing the arginine (R) at amino acid position 1780 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Apr 08, 2020

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Uncertain:1

May 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Developmental and epileptic encephalopathy, 42

Uncertain:1

Jun 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant c.5336G>A (p.Arg1779Gln) in the CACNA1A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency (0.0003%) in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Arg at position 1779 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. Computational evidence (Polyphen, SIFT and MutationTaster) predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Arg1779Gln in CACNA1A is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

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

Benign:1

Jul 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0077

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

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.056

LIST_S2

Uncertain

0.97

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

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.12

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

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

0.50

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

PhyloP100

2.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.34

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

REVEL

Benign

0.21

Sift

Benign

0.47

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

Sift4G

Benign

0.51

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

Vest4

0.046

MutPred

0.65

.;.;Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);.;.;Loss of helix (P = 0.0558);.;.;.;Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);.;Loss of helix (P = 0.0558);.;.;.;.;.;

MVP

0.72

MPC

1.4

ClinPred

0.082

GERP RS

2.6

Varity_R

0.025

gMVP

0.42

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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19-13231774-C-T

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