19-13207645-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001127222.2(CACNA1A):c.7189G>A(p.Val2397Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,464,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2397A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.416

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Genomics England PanelApp
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
developmental and epileptic encephalopathy, 42
Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
migraine, familial hemiplegic, 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
spinocerebellar ataxia type 6
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14637965).

BP6

Variant 19-13207645-C-T is Benign according to our data. Variant chr19-13207645-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446944.

BS2

High AC in GnomAd4 at 33 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127222.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1A	NM_001127222.2	MANE Select	c.7189G>A	p.Val2397Met	missense	Exon 47 of 47	NP_001120694.1	O00555-8
CACNA1A	NM_001127221.2	MANE Plus Clinical	c.*401G>A		3_prime_UTR	Exon 47 of 47	NP_001120693.1	O00555-3
CACNA1A	NM_023035.3		c.7207G>A	p.Val2403Met	missense	Exon 48 of 48	NP_075461.2	A0A087WW63

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.7189G>A	p.Val2397Met	missense	Exon 47 of 47	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1	TSL:5	c.7207G>A	p.Val2403Met	missense	Exon 48 of 48	ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7	TSL:5	c.7195G>A	p.Val2399Met	missense	Exon 47 of 47	ENSP00000460092.3	A0A1C7CYY9

Frequencies

GnomAD3 genomes

AF:

0.000218

AC:

AN:

151600

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000957

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000398

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000153

AC:

AN:

84882

AF XY:

0.000207

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000438

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000215

AC:

282

AN:

1313088

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

131

AN XY:

647430

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26260

American (AMR)

AF:

0.00

AC:

AN:

27162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22612

East Asian (EAS)

AF:

0.00

AC:

AN:

28090

South Asian (SAS)

AF:

0.00

AC:

AN:

72742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38256

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3886

European-Non Finnish (NFE)

AF:

0.000263

AC:

274

AN:

1040312

Other (OTH)

AF:

0.000149

AC:

AN:

53768

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000218

AC:

AN:

151708

Hom.:

Cov.:

AF XY:

0.000189

AC XY:

AN XY:

74136

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.000262

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000957

AC:

AN:

10450

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000398

AC:

AN:

67778

Other (OTH)

AF:

0.00

AC:

AN:

2100

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

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:

0.00

Hom.:

Bravo

AF:

0.000261

ExAC

AF:

0.0000514

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.24

CADD

Benign

8.8

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.029

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.15

MetaSVM

Uncertain

-0.0068

PhyloP100

-0.42

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.13

REVEL

Benign

0.20

Sift

Benign

0.049

Sift4G

Benign

0.20

Vest4

0.059

MutPred

0.29

Loss of glycosylation at S2398 (P = 0.085)

MVP

0.72

MPC

0.29

ClinPred

0.036

GERP RS

-1.6

Varity_R

0.072

gMVP

0.14

Mutation Taster

=97/3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over