rs1265762175

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000719.7(CACNA1C):c.209A>G(p.Asn70Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,609,146 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 (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.11

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.298137).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.299A>G	p.Asn100Ser	missense_variant	Exon 2 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.299A>G	p.Asn100Ser	missense_variant	Exon 2 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.299A>G	p.Asn100Ser	missense_variant	Exon 2 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.299A>G	p.Asn100Ser	missense_variant	Exon 2 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.299A>G	p.Asn100Ser	missense_variant	Exon 2 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.299A>G	p.Asn100Ser	missense_variant	Exon 2 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.209A>G	p.Asn70Ser	missense_variant	Exon 2 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1 link	c.158A>G	p.Asn53Ser	missense_variant	Exon 1 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6 link	n.209A>G		non_coding_transcript_exon_variant	Exon 2 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1456910

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724650

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33428

American (AMR)

AF:

0.00

AC:

AN:

44204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25994

East Asian (EAS)

AF:

0.00

AC:

AN:

39606

South Asian (SAS)

AF:

0.00

AC:

AN:

85634

European-Finnish (FIN)

AF:

0.0000196

AC:

AN:

51110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110946

Other (OTH)

AF:

0.00

AC:

AN:

60226

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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2094

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

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:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:1

Mar 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 70 of the CACNA1C protein (p.Asn70Ser). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 456951). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

CardioboostArm

Benign

0.000038

BayesDel_addAF

Uncertain

0.056

BayesDel_noAF

Benign

-0.16

CADD

Benign

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.0090

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

Eigen

Benign

-0.11

Eigen_PC

Benign

0.039

FATHMM_MKL

Uncertain

0.97

M_CAP

Benign

0.071

MetaRNN

Benign

0.30

T;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

0.65

MutationAssessor

Benign

-0.34

.;.;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;.;.;.

PhyloP100

6.1

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.9

D;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.23, 0.0050, 0.022, 0.57, 0.024, 0.63

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

Vest4

0.44, 0.47, 0.45, 0.49, 0.49, 0.45, 0.48, 0.48, 0.49, 0.44, 0.45, 0.46, 0.48, 0.42, 0.49, 0.40, 0.51, 0.48, 0.44

MutPred

0.31

.;Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);Gain of catalytic residue at G66 (P = 6e-04);

MVP

0.90

MPC

0.86

ClinPred

0.34

GERP RS

5.6

PromoterAI

0.0012

Neutral

(source)

gMVP

0.49

Mutation Taster

=89/11

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