rs121908224

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP3_ModeratePP5_Moderate

The NM_001127222.2(CACNA1A):c.5080G>T(p.Val1694Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1694I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.08

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_pathogenic. The variant received 8 ACMG points.

PM1

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

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.929

PP5

Variant 19-13235262-C-A is Pathogenic according to our data. Variant chr19-13235262-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2925638.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.5080G>T	p.Val1694Phe	missense_variant	Exon 33 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.5083G>T	p.Val1695Phe	missense_variant	Exon 33 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.5080G>T	p.Val1694Phe	missense_variant	Exon 33 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.5083G>T	p.Val1695Phe	missense_variant	Exon 33 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.5098G>T	p.Val1700Phe	missense_variant	Exon 34 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.5086G>T	p.Val1696Phe	missense_variant	Exon 33 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.5083G>T	p.Val1695Phe	missense_variant	Exon 33 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.5083G>T	p.Val1695Phe	missense_variant	Exon 33 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.5083G>T	p.Val1695Phe	missense_variant	Exon 33 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.4942G>T	p.Val1648Phe	missense_variant	Exon 32 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.5083G>T	p.Val1695Phe	missense_variant	Exon 33 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.5098G>T	p.Val1700Phe	missense_variant	Exon 34 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.5089G>T	p.Val1697Phe	missense_variant	Exon 34 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.5086G>T	p.Val1696Phe	missense_variant	Exon 33 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.5083G>T	p.Val1695Phe	missense_variant	Exon 33 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.5083G>T	p.Val1695Phe	missense_variant	Exon 33 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.5083G>T		non_coding_transcript_exon_variant	Exon 33 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.*261G>T		non_coding_transcript_exon_variant	Exon 34 of 47			ENSP00000519091.1
CACNA1A	ENST00000713789.1 link	n.*261G>T		3_prime_UTR_variant	Exon 34 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1442784

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715984

African (AFR)

AF:

0.00

AC:

AN:

33026

American (AMR)

AF:

0.00

AC:

AN:

40806

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25756

East Asian (EAS)

AF:

0.00

AC:

AN:

38820

South Asian (SAS)

AF:

0.00

AC:

AN:

83696

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102936

Other (OTH)

AF:

0.00

AC:

AN:

59754

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Pathogenic:1

Oct 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1695 of the CACNA1A protein (p.Val1695Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CACNA1A-related conditions (PMID: 18498393). In at least one individual the variant was observed to be de novo. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1A protein function. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.56

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

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

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.93

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

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

PhyloP100

6.1

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-4.5

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

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Vest4

0.84

MutPred

0.70

.;.;Loss of catalytic residue at V1695 (P = 0.1017);Loss of catalytic residue at V1695 (P = 0.1017);Loss of catalytic residue at V1695 (P = 0.1017);.;.;Loss of catalytic residue at V1695 (P = 0.1017);.;.;.;Loss of catalytic residue at V1695 (P = 0.1017);Loss of catalytic residue at V1695 (P = 0.1017);.;Loss of catalytic residue at V1695 (P = 0.1017);.;.;.;.;

MVP

0.98

MPC

1.6

ClinPred

1.0

GERP RS

5.1

Varity_R

0.83

gMVP

0.99

Mutation Taster

=0/100

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