12-2674532-G-C

Variant names:

Variant summary

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

The ENST00000344100.7(CACNA1C):c.4841G>C(p.Arg1614Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 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. R1614C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

CACNA1C
ENST00000344100.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.589

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 links:

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

ITFG2-AS1 links:

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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=0.0688003).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.4727-9G>C		intron_variant	Intron 38 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.4727-9G>C		intron_variant	Intron 38 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000344100.7 link	c.4841G>C	p.Arg1614Pro	missense_variant	Exon 39 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000399621.5 link	c.4775G>C	p.Arg1592Pro	missense_variant	Exon 39 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.4775G>C	p.Arg1592Pro	missense_variant	Exon 39 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.4775G>C	p.Arg1592Pro	missense_variant	Exon 39 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399591.5 link	c.4742G>C	p.Arg1581Pro	missense_variant	Exon 38 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.4742G>C	p.Arg1581Pro	missense_variant	Exon 38 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.4736G>C	p.Arg1579Pro	missense_variant	Exon 38 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399603.6 link	c.4727-9G>C		intron_variant	Intron 38 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.4727-9G>C		intron_variant	Intron 38 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.4961-9G>C		intron_variant	Intron 40 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.4727-9G>C		intron_variant	Intron 38 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.4694-9G>C		intron_variant	Intron 37 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.4892-9G>C		intron_variant	Intron 39 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.4871-9G>C		intron_variant	Intron 40 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000327702.12 link	c.4727-9G>C		intron_variant	Intron 38 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.4727-9G>C		intron_variant	Intron 38 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.4817-9G>C		intron_variant	Intron 38 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.4817-9G>C		intron_variant	Intron 38 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.4817-9G>C		intron_variant	Intron 38 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.4817-9G>C		intron_variant	Intron 38 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.4811-9G>C		intron_variant	Intron 39 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.4802-9G>C		intron_variant	Intron 39 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.4787-9G>C		intron_variant	Intron 39 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399629.5 link	c.4778-9G>C		intron_variant	Intron 38 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.4769-9G>C		intron_variant	Intron 38 of 46			ENSP00000507898.1
CACNA1C	ENST00000399597.5 link	c.4727-9G>C		intron_variant	Intron 38 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.4727-9G>C		intron_variant	Intron 38 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.4727-9G>C		intron_variant	Intron 38 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.4727-9G>C		intron_variant	Intron 38 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.4727-9G>C		intron_variant	Intron 38 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.4718-9G>C		intron_variant	Intron 38 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.4694-9G>C		intron_variant	Intron 37 of 45			ENSP00000507309.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1402646

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

692200

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31810

American (AMR)

AF:

0.00

AC:

AN:

36048

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25176

East Asian (EAS)

AF:

0.00

AC:

AN:

36106

South Asian (SAS)

AF:

0.00

AC:

AN:

79392

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1080768

Other (OTH)

AF:

0.0000172

AC:

AN:

58176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.35

CADD

Benign

2.1

(source)

DANN

Benign

0.80

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.042

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.069

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

MetaSVM

Benign

-0.29

PhyloP100

-0.59

PROVEAN

Benign

-0.11

N;N;N;N;N;N;N

REVEL

Benign

0.13

Sift

Uncertain

0.0050

D;D;D;D;D;D;D

Sift4G

Benign

0.14

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

Polyphen

0.0

B;B;B;B;B;B;B

Vest4

0.078

MutPred

0.38

.;.;.;.;Gain of catalytic residue at R1614 (P = 0.001);.;.;

MVP

0.20

ClinPred

0.061

GERP RS

-8.6

Mutation Taster

=93/7

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over