rs760816963

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001127222.2(CACNA1A):c.2404C>T(p.Arg802Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R802S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.50

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.2404C>T	p.Arg802Cys	missense_variant	Exon 19 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.2407C>T	p.Arg803Cys	missense_variant	Exon 19 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.2404C>T	p.Arg802Cys	missense_variant	Exon 19 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.2407C>T	p.Arg803Cys	missense_variant	Exon 19 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.2416C>T	p.Arg806Cys	missense_variant	Exon 19 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.2410C>T	p.Arg804Cys	missense_variant	Exon 19 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.2407C>T	p.Arg803Cys	missense_variant	Exon 19 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.2407C>T	p.Arg803Cys	missense_variant	Exon 19 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.2407C>T	p.Arg803Cys	missense_variant	Exon 19 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.2266C>T	p.Arg756Cys	missense_variant	Exon 18 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.2407C>T	p.Arg803Cys	missense_variant	Exon 19 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.2416C>T	p.Arg806Cys	missense_variant	Exon 19 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.2407C>T	p.Arg803Cys	missense_variant	Exon 19 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.2410C>T	p.Arg804Cys	missense_variant	Exon 19 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.2407C>T	p.Arg803Cys	missense_variant	Exon 19 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.2407C>T	p.Arg803Cys	missense_variant	Exon 19 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.2407C>T		non_coding_transcript_exon_variant	Exon 19 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.2404C>T		non_coding_transcript_exon_variant	Exon 19 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1458048

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725502

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49806

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111840

Other (OTH)

AF:

0.00

AC:

AN:

60346

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 06, 2022

GeneDx

Significance:Uncertain significance

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; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.092

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

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.97

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

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.71

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

MetaSVM

Pathogenic

0.79

MutationAssessor

Uncertain

2.3

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

PhyloP100

2.5

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-5.8

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

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.027

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

Vest4

0.62

MutPred

0.31

.;.;Loss of MoRF binding (P = 0.0073);Loss of MoRF binding (P = 0.0073);Loss of MoRF binding (P = 0.0073);.;Loss of MoRF binding (P = 0.0073);.;.;Loss of MoRF binding (P = 0.0073);Loss of MoRF binding (P = 0.0073);.;Loss of MoRF binding (P = 0.0073);.;Loss of MoRF binding (P = 0.0073);

MVP

0.94

MPC

2.6

ClinPred

0.98

GERP RS

2.9

Varity_R

0.45

gMVP

0.81

Mutation Taster

=45/55

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over