NM_000719.7:c.4941C>G

Variant names:

Variant summary

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

The NM_000719.7(CACNA1C):c.4941C>G(p.Asn1647Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N1647N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.60

Publications

1 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:

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

CACNA1C-AS1 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=0.2221426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.4941C>G	p.Asn1647Lys	missense_variant	Exon 40 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.4941C>G	p.Asn1647Lys	missense_variant	Exon 40 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.4941C>G	p.Asn1647Lys	missense_variant	Exon 40 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.4941C>G	p.Asn1647Lys	missense_variant	Exon 40 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.5175C>G	p.Asn1725Lys	missense_variant	Exon 42 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.4941C>G	p.Asn1647Lys	missense_variant	Exon 40 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.4908C>G	p.Asn1636Lys	missense_variant	Exon 39 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.5106C>G	p.Asn1702Lys	missense_variant	Exon 41 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.5085C>G	p.Asn1695Lys	missense_variant	Exon 42 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.5064C>G	p.Asn1688Lys	missense_variant	Exon 40 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.4941C>G	p.Asn1647Lys	missense_variant	Exon 40 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.4941C>G	p.Asn1647Lys	missense_variant	Exon 40 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.5031C>G	p.Asn1677Lys	missense_variant	Exon 40 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.5031C>G	p.Asn1677Lys	missense_variant	Exon 40 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.5031C>G	p.Asn1677Lys	missense_variant	Exon 40 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.5031C>G	p.Asn1677Lys	missense_variant	Exon 40 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.5025C>G	p.Asn1675Lys	missense_variant	Exon 41 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.5016C>G	p.Asn1672Lys	missense_variant	Exon 41 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.5001C>G	p.Asn1667Lys	missense_variant	Exon 41 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.4998C>G	p.Asn1666Lys	missense_variant	Exon 40 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.4998C>G	p.Asn1666Lys	missense_variant	Exon 40 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.4998C>G	p.Asn1666Lys	missense_variant	Exon 40 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.4992C>G	p.Asn1664Lys	missense_variant	Exon 40 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.4983C>G	p.Asn1661Lys	missense_variant	Exon 40 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.4965C>G	p.Asn1655Lys	missense_variant	Exon 39 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.4965C>G	p.Asn1655Lys	missense_variant	Exon 39 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.4959C>G	p.Asn1653Lys	missense_variant	Exon 39 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.4941C>G	p.Asn1647Lys	missense_variant	Exon 40 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.4941C>G	p.Asn1647Lys	missense_variant	Exon 40 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.4941C>G	p.Asn1647Lys	missense_variant	Exon 40 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.4941C>G	p.Asn1647Lys	missense_variant	Exon 40 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.4941C>G	p.Asn1647Lys	missense_variant	Exon 40 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.4932C>G	p.Asn1644Lys	missense_variant	Exon 40 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.4908C>G	p.Asn1636Lys	missense_variant	Exon 39 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461362

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726912

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111774

Other (OTH)

AF:

0.00

AC:

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:1

Feb 14, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CACNA1C-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with lysine at codon 1647 of the CACNA1C protein (p.Asn1647Lys). The asparagine residue is moderately conserved and there is a moderate physicochemical difference between asparagine and lysine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

CardioboostArm

Benign

0.0000045

BayesDel_addAF

Benign

-0.0080

BayesDel_noAF

Benign

-0.25

CADD

Benign

8.2

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.054

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

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.24

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.22

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

MetaSVM

Uncertain

0.46

MutationAssessor

Benign

1.6

.;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

-1.6

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.

REVEL

Uncertain

0.33

Sift

Benign

0.036

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.

Sift4G

Benign

0.16

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D

Polyphen

0.89, 0.46, 0.0030, 0.17, 0.0020, 0.0090, 0.0050, 0.0010, 0.91, 0.0040, 0.0

.;P;P;B;B;B;B;B;B;B;B;B;P;B;B;.;B;B;.;.;.;B;.

Vest4

0.29

MutPred

0.34

.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at K1690 (P = 6e-04);.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.84

MPC

1.3

ClinPred

0.40

GERP RS

-2.5

gMVP

0.84

Mutation Taster

=56/44

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over