rs973900517

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001127222.2(CACNA1A):c.7197G>C(p.Glu2399Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000135 in 1,477,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.74

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:

ENSG00000300728 (HGNC:):

ENSG00000300728 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25388917).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.7197G>C	p.Glu2399Asp	missense_variant	Exon 47 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.*409G>C		3_prime_UTR_variant	Exon 47 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.7197G>C	p.Glu2399Asp	missense_variant	Exon 47 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1 link	c.7215G>C	p.Glu2405Asp	missense_variant	Exon 48 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.7203G>C	p.Glu2401Asp	missense_variant	Exon 47 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.7200G>C	p.Glu2400Asp	missense_variant	Exon 47 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.7200G>C	p.Glu2400Asp	missense_variant	Exon 47 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.7164G>C	p.Glu2388Asp	missense_variant	Exon 46 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.7059G>C	p.Glu2353Asp	missense_variant	Exon 46 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636768.2 link	n.*1458G>C		non_coding_transcript_exon_variant	Exon 45 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.*2376G>C		non_coding_transcript_exon_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000638009.2 link	c.*409G>C		3_prime_UTR_variant	Exon 47 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000636389.1 link	c.*283G>C		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.*409G>C		3_prime_UTR_variant	Exon 48 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000635895.1 link	c.*409G>C		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000636768.2 link	n.*1458G>C		3_prime_UTR_variant	Exon 45 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.*2376G>C		3_prime_UTR_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000637276.1 link	c.*409G>C		downstream_gene_variant		5		ENSP00000489777.1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151632

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

7.54e-7

AC:

AN:

1325740

Hom.:

Cov.:

AF XY:

0.00000153

AC XY:

AN XY:

654082

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26490

American (AMR)

AF:

0.00

AC:

AN:

28946

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23002

East Asian (EAS)

AF:

0.00

AC:

AN:

28710

South Asian (SAS)

AF:

0.00

AC:

AN:

73972

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39040

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3980

European-Non Finnish (NFE)

AF:

9.55e-7

AC:

AN:

1047138

Other (OTH)

AF:

0.00

AC:

AN:

54462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.00000659

AC:

AN:

151632

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74044

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41354

American (AMR)

AF:

0.00

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10442

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67818

Other (OTH)

AF:

0.00

AC:

AN:

2084

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 21, 2018

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.011

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

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.67

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

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.25

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

MetaSVM

Benign

-0.41

PhyloP100

1.7

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.51

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

REVEL

Uncertain

0.32

Sift

Benign

0.15

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

Sift4G

Benign

0.16

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

Vest4

0.065

MutPred

0.28

.;Loss of catalytic residue at E2399 (P = 0.1053);.;.;.;.;.;.;.;.;

MVP

0.70

MPC

0.44

ClinPred

0.35

GERP RS

-1.5

Varity_R

0.048

gMVP

0.17

Mutation Taster

=91/9

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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