rs60106875

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 ENST00000683824.1(CACNA1C):c.1490C>A(p.Pro497Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000159 in 627,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P497L) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

CACNA1C
ENST00000683824.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.42

Publications

0 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: Ambry Genetics, Orphanet, G2P, 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: Orphanet, ClinGen
Brugada syndrome 3
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, 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: Ambry Genetics, ClinGen

CACNA1C 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=0.22090816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1391-2484C>A		intron_variant	Intron 9 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.1391-2484C>A		intron_variant	Intron 9 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000683824.1 link	c.1490C>A	p.Pro497Gln	missense_variant	Exon 10 of 48			ENSP00000507867.1
CACNA1C	ENST00000335762.10 link	c.1400C>A	p.Pro467Gln	missense_variant	Exon 10 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000682336.1 link	c.1400C>A	p.Pro467Gln	missense_variant	Exon 10 of 47			ENSP00000507898.1
CACNA1C	ENST00000399603.6 link	c.1391-2484C>A		intron_variant	Intron 9 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.1391-2484C>A		intron_variant	Intron 9 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.1481-2484C>A		intron_variant	Intron 9 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.1391-2484C>A		intron_variant	Intron 9 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.1391-2484C>A		intron_variant	Intron 9 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000347598.9 link	c.1391-2484C>A		intron_variant	Intron 9 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.1391-2484C>A		intron_variant	Intron 9 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.1391-2484C>A		intron_variant	Intron 9 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.1391-2484C>A		intron_variant	Intron 9 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.1481-2484C>A		intron_variant	Intron 9 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.1481-2484C>A		intron_variant	Intron 9 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.1481-2484C>A		intron_variant	Intron 9 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.1481-2484C>A		intron_variant	Intron 9 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.1391-2484C>A		intron_variant	Intron 9 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000399606.5 link	c.1391-2484C>A		intron_variant	Intron 9 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.1391-2484C>A		intron_variant	Intron 9 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.1391-2484C>A		intron_variant	Intron 9 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.1391-2484C>A		intron_variant	Intron 9 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.1391-2484C>A		intron_variant	Intron 9 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000399591.5 link	c.1391-2484C>A		intron_variant	Intron 9 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.1391-2484C>A		intron_variant	Intron 9 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.1391-2484C>A		intron_variant	Intron 9 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.1391-2484C>A		intron_variant	Intron 9 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.1391-2484C>A		intron_variant	Intron 9 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.1391-2484C>A		intron_variant	Intron 9 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.1391-2484C>A		intron_variant	Intron 9 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.1391-2484C>A		intron_variant	Intron 9 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.1382-2484C>A		intron_variant	Intron 9 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.1391-2484C>A		intron_variant	Intron 9 of 45			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.1114-2484C>A		intron_variant	Intron 7 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000159

AC:

AN:

627436

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

341848

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17694

American (AMR)

AF:

0.00

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:

0.0000143

AC:

AN:

69778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52014

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4148

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

349950

Other (OTH)

AF:

0.00

AC:

AN:

33066

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.010

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.92

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.22

MetaSVM

Uncertain

-0.11

PhyloP100

1.4

PROVEAN

Benign

-0.54

REVEL

Uncertain

0.40

Sift

Benign

0.59

Sift4G

Benign

0.56

Vest4

0.37

MutPred

0.29

Loss of loop (P = 0.0374);

MVP

0.79

ClinPred

0.13

GERP RS

3.2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over