rs369438564

Variant names:

Variant summary

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

The NM_000719.7(CACNA1C):c.5644T>C(p.Ser1882Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000167 in 1,613,636 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.09

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:

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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21634239).

BP6

Variant 12-2685806-T-C is Benign according to our data. Variant chr12-2685806-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197498.

BS2

High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.5644T>C	p.Ser1882Pro	missense_variant	Exon 44 of 47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.5644T>C	p.Ser1882Pro	missense_variant	Exon 44 of 47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.5644T>C	p.Ser1882Pro	missense_variant	Exon 44 of 47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.5644T>C	p.Ser1882Pro	missense_variant	Exon 44 of 47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.5983T>C	p.Ser1995Pro	missense_variant	Exon 47 of 50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.5857T>C	p.Ser1953Pro	missense_variant	Exon 45 of 48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.5824T>C	p.Ser1942Pro	missense_variant	Exon 44 of 47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.5809T>C	p.Ser1937Pro	missense_variant	Exon 45 of 48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.5788T>C	p.Ser1930Pro	missense_variant	Exon 46 of 49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.5767T>C	p.Ser1923Pro	missense_variant	Exon 44 of 47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.5749T>C	p.Ser1917Pro	missense_variant	Exon 45 of 48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.5749T>C	p.Ser1917Pro	missense_variant	Exon 45 of 48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.5734T>C	p.Ser1912Pro	missense_variant	Exon 44 of 47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.5734T>C	p.Ser1912Pro	missense_variant	Exon 44 of 47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.5734T>C	p.Ser1912Pro	missense_variant	Exon 44 of 47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.5734T>C	p.Ser1912Pro	missense_variant	Exon 44 of 47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.5728T>C	p.Ser1910Pro	missense_variant	Exon 45 of 48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.5719T>C	p.Ser1907Pro	missense_variant	Exon 45 of 48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.5704T>C	p.Ser1902Pro	missense_variant	Exon 45 of 48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.5701T>C	p.Ser1901Pro	missense_variant	Exon 44 of 47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.5701T>C	p.Ser1901Pro	missense_variant	Exon 44 of 47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.5701T>C	p.Ser1901Pro	missense_variant	Exon 44 of 47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.5695T>C	p.Ser1899Pro	missense_variant	Exon 44 of 47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.5686T>C	p.Ser1896Pro	missense_variant	Exon 44 of 47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.5668T>C	p.Ser1890Pro	missense_variant	Exon 43 of 46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.5668T>C	p.Ser1890Pro	missense_variant	Exon 43 of 46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.5662T>C	p.Ser1888Pro	missense_variant	Exon 43 of 46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.5644T>C	p.Ser1882Pro	missense_variant	Exon 44 of 47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.5644T>C	p.Ser1882Pro	missense_variant	Exon 44 of 47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.5644T>C	p.Ser1882Pro	missense_variant	Exon 44 of 47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.5644T>C	p.Ser1882Pro	missense_variant	Exon 44 of 47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.5644T>C	p.Ser1882Pro	missense_variant	Exon 44 of 47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.5635T>C	p.Ser1879Pro	missense_variant	Exon 44 of 47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.5611T>C	p.Ser1871Pro	missense_variant	Exon 43 of 46			ENSP00000507309.1	Q13936-19

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000149

AC:

AN:

248936

AF XY:

0.000163

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000231

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000170

AC:

248

AN:

1461388

Hom.:

Cov.:

AF XY:

0.000182

AC XY:

132

AN XY:

726982

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33472

American (AMR)

AF:

0.000268

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000204

AC:

227

AN:

1111612

Other (OTH)

AF:

0.000133

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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:

0.000145

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41550

American (AMR)

AF:

0.000262

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68014

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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:

0.0000955

Hom.:

Bravo

AF:

0.000132

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.000149

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Oct 28, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 16, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25633834) -

Long QT syndrome

Benign:1

Dec 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Oct 25, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

CardioboostArm

Benign

0.000049

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.016

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

Eigen

Benign

-0.023

Eigen_PC

Benign

-0.019

FATHMM_MKL

Uncertain

0.96

M_CAP

Uncertain

0.15

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

Benign

-0.70

PhyloP100

6.1

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.6

D;N;N;N;D;N;D;D;N;N;D;D;N;N;N;D;N;D;N;D;D;D;.

REVEL

Benign

0.28

Sift

Benign

0.10

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;T;.

Sift4G

Benign

0.11

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

Polyphen

0.0, 0.31, 0.18, 0.86, 0.88, 0.78, 1.0, 0.94, 0.93, 0.70, 0.87, 0.86, 0.98

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

Vest4

0.68

MVP

0.74

MPC

0.24

ClinPred

0.13

GERP RS

4.3

gMVP

0.59

Mutation Taster

=52/48

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over