chr19-13209459-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001127222.2(CACNA1A):c.6379G>A(p.Val2127Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000147 in 1,363,058 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).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.31

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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.058272302).

BP6

Variant 19-13209459-C-T is Benign according to our data. Variant chr19-13209459-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 476271.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.6379G>A	p.Val2127Met	missense_variant	Exon 45 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.6382G>A	p.Val2128Met	missense_variant	Exon 45 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.6379G>A	p.Val2127Met	missense_variant	Exon 45 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.6382G>A	p.Val2128Met	missense_variant	Exon 45 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.6397G>A	p.Val2133Met	missense_variant	Exon 46 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.6385G>A	p.Val2129Met	missense_variant	Exon 45 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.6382G>A	p.Val2128Met	missense_variant	Exon 45 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.6382G>A	p.Val2128Met	missense_variant	Exon 45 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.6346G>A	p.Val2116Met	missense_variant	Exon 44 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.6241G>A	p.Val2081Met	missense_variant	Exon 44 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.6382G>A	p.Val2128Met	missense_variant	Exon 45 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.6397G>A	p.Val2133Met	missense_variant	Exon 46 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.6388G>A	p.Val2130Met	missense_variant	Exon 46 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.6385G>A	p.Val2129Met	missense_variant	Exon 45 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.6382G>A	p.Val2128Met	missense_variant	Exon 45 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.6346G>A	p.Val2116Met	missense_variant	Exon 44 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.*645G>A		non_coding_transcript_exon_variant	Exon 43 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.*1558G>A		non_coding_transcript_exon_variant	Exon 45 of 47			ENSP00000519091.1
CACNA1A	ENST00000636768.2 link	n.*645G>A		3_prime_UTR_variant	Exon 43 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.*1558G>A		3_prime_UTR_variant	Exon 45 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.0000445

AC:

AN:

67394

AF XY:

0.0000559

show subpopulations

Gnomad AFR exome

AF:

0.000396

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000192

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000107

AC:

AN:

1210980

Hom.:

Cov.:

AF XY:

0.00000686

AC XY:

AN XY:

582872

show subpopulations

African (AFR)

AF:

0.000157

AC:

AN:

25442

American (AMR)

AF:

0.00

AC:

AN:

15116

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16272

East Asian (EAS)

AF:

0.0000325

AC:

AN:

30772

South Asian (SAS)

AF:

0.0000230

AC:

AN:

43426

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41916

Middle Eastern (MID)

AF:

0.000224

AC:

AN:

4474

European-Non Finnish (NFE)

AF:

0.00000406

AC:

AN:

984540

Other (OTH)

AF:

0.0000408

AC:

AN:

49022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.0000460

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41418

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

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:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.546

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000523

Hom.:

Bravo

AF:

0.0000793

ESP6500AA

AF:

0.000251

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000178

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Dec 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.6382G>A (p.V2128M) alteration is located in exon 45 (coding exon 45) of the CACNA1A gene. This alteration results from a G to A substitution at nucleotide position 6382, causing the valine (V) at amino acid position 2128 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Benign:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.019

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

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.78

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

M_CAP

Benign

0.049

MetaRNN

Benign

0.058

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

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.41

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

PhyloP100

1.3

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.85

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

REVEL

Benign

0.25

Sift

Benign

0.074

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

Sift4G

Benign

0.075

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

Vest4

0.27

MVP

0.79

MPC

0.27

ClinPred

0.050

GERP RS

0.91

Varity_R

0.094

gMVP

0.31

Mutation Taster

=95/5

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over