rs1365721398

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_001127222.2(CACNA1A):c.578C>T(p.Thr193Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000127 in 1,579,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T193T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 9.77

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: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001127222.2

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.923

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.578C>T	p.Thr193Met	missense_variant	Exon 4 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.578C>T	p.Thr193Met	missense_variant	Exon 4 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.578C>T	p.Thr193Met	missense_variant	Exon 4 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.578C>T	p.Thr193Met	missense_variant	Exon 4 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.578C>T	p.Thr193Met	missense_variant	Exon 4 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.578C>T	p.Thr193Met	missense_variant	Exon 4 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.578C>T	p.Thr193Met	missense_variant	Exon 4 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.578C>T	p.Thr193Met	missense_variant	Exon 4 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.578C>T	p.Thr193Met	missense_variant	Exon 4 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.437C>T	p.Thr146Met	missense_variant	Exon 3 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.578C>T	p.Thr193Met	missense_variant	Exon 4 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.578C>T	p.Thr193Met	missense_variant	Exon 4 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.578C>T	p.Thr193Met	missense_variant	Exon 4 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.578C>T	p.Thr193Met	missense_variant	Exon 4 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.578C>T	p.Thr193Met	missense_variant	Exon 4 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.578C>T	p.Thr193Met	missense_variant	Exon 4 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.578C>T		non_coding_transcript_exon_variant	Exon 4 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.578C>T		non_coding_transcript_exon_variant	Exon 4 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD4 exome

AF:

7.00e-7

AC:

AN:

1427838

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

706840

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32740

American (AMR)

AF:

0.00

AC:

AN:

39448

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25500

East Asian (EAS)

AF:

0.00

AC:

AN:

37908

South Asian (SAS)

AF:

0.00

AC:

AN:

81086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50990

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

9.13e-7

AC:

AN:

1095196

Other (OTH)

AF:

0.00

AC:

AN:

59242

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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:

0.00000657

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74288

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41430

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 27, 2017

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Uncertain:1

Apr 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 193 of the CACNA1A protein (p.Thr193Met). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 446934). 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 with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

not provided

Uncertain:1

Dec 26, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Missense variants in nearby residues reported in the Human Gene Mutation Database (Stenson et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0

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

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.92

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.0

.;L;.;.;L;.;.;L;.;.;.;.;L;.;.

PhyloP100

9.8

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.0

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

REVEL

Benign

0.0

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.031

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

Vest4

0.59

ClinPred

0.99

GERP RS

4.9

Varity_R

0.63

gMVP

0.90

Mutation Taster

=11/89

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over