Genetic Variant CACNA1C:p.Pro497Leu (chr12-2547459-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000683824.1(CACNA1C):c.1490C>T(p.Pro497Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 779,644 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0045 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00055 ( 1 hom. )

Consequence

CACNA1C
ENST00000683824.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.42

Publications

4 publications found

Variant links:

Genes affected

CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]

CACNA1C Gene-Disease associations (from GenCC):

Timothy syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
long QT syndrome
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
long QT syndrome 8
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
Brugada syndrome
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: ClinGen, Orphanet
Brugada syndrome 3
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
short QT syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Ambry Genetics

CACNA1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057228208).

BP6

Variant 12-2547459-C-T is Benign according to our data. Variant chr12-2547459-C-T is described in ClinVar as Benign. ClinVar VariationId is 191564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00453 (690/152208) while in subpopulation AFR AF = 0.0159 (661/41514). AF 95% confidence interval is 0.0149. There are 2 homozygotes in GnomAd4. There are 334 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 690 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000683824.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CACNA1C	NM_000719.7	MANE Select	c.1391-2484C>T	intron	N/A	NP_000710.5
CACNA1C	NM_001167623.2	MANE Plus Clinical	c.1391-2484C>T	intron	N/A	NP_001161095.1
CACNA1C	NM_199460.4		c.1391-2484C>T	intron	N/A	NP_955630.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1C	ENST00000683824.1		c.1490C>T	p.Pro497Leu	missense	Exon 10 of 48	ENSP00000507867.1
CACNA1C	ENST00000335762.10	TSL:5	c.1400C>T	p.Pro467Leu	missense	Exon 10 of 48	ENSP00000336982.5
CACNA1C	ENST00000682336.1		c.1400C>T	p.Pro467Leu	missense	Exon 10 of 47	ENSP00000507898.1

Frequencies

GnomAD3 genomes

AF:

0.00455

AC:

692

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0160

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.000961

AC:

232

AN:

241472

AF XY:

0.000792

show subpopulations

Gnomad AFR exome

AF:

0.0148

Gnomad AMR exome

AF:

0.000436

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000466

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000548

AC:

344

AN:

627436

Hom.:

Cov.:

AF XY:

0.000445

AC XY:

152

AN XY:

341848

show subpopulations

African (AFR)

AF:

0.0148

AC:

262

AN:

17694

American (AMR)

AF:

0.000777

AC:

AN:

43734

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20982

East Asian (EAS)

AF:

0.00

AC:

AN:

36070

South Asian (SAS)

AF:

0.0000430

AC:

AN:

69778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52014

Middle Eastern (MID)

AF:

0.000241

AC:

AN:

4148

European-Non Finnish (NFE)

AF:

0.0000400

AC:

AN:

349950

Other (OTH)

AF:

0.000907

AC:

AN:

33066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.00453

AC:

690

AN:

152208

Hom.:

Cov.:

AF XY:

0.00449

AC XY:

334

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.0159

AC:

661

AN:

41514

American (AMR)

AF:

0.00105

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68008

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

131

164

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:

0.00127

Hom.:

Bravo

AF:

0.00473

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0120

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00116

AC:

135

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.0074

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.078

FATHMM_MKL

Uncertain

0.81

MetaRNN

Benign

0.0057

MetaSVM

Uncertain

-0.012

PhyloP100

1.4

PROVEAN

Benign

0.25

REVEL

Benign

0.18

Sift

Benign

0.32

Sift4G

Benign

0.42

Vest4

0.30

MVP

0.61

ClinPred

0.015

GERP RS

3.2

Mutation Taster

=92/8

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over