rs769703001

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_000719.7(CACNA1C):c.65G>A(p.Ser22Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000191 in 1,572,518 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S22I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 6.29

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: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23682973).

BP6

Variant 12-2115239-G-A is Benign according to our data. Variant chr12-2115239-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1754411.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.65G>A	p.Ser22Asn	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.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.155G>A	p.Ser52Asn	missense_variant	Exon 2 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.155G>A	p.Ser52Asn	missense_variant	Exon 2 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.155G>A	p.Ser52Asn	missense_variant	Exon 2 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.155G>A	p.Ser52Asn	missense_variant	Exon 2 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.155G>A	p.Ser52Asn	missense_variant	Exon 2 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.155G>A	p.Ser52Asn	missense_variant	Exon 2 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.65G>A	p.Ser22Asn	missense_variant	Exon 2 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1 link	c.14G>A	p.Ser5Asn	missense_variant	Exon 1 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6 link	n.65G>A		non_coding_transcript_exon_variant	Exon 2 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.04e-7

AC:

AN:

1420276

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

701308

show subpopulations

African (AFR)

AF:

0.0000309

AC:

AN:

32334

American (AMR)

AF:

0.00

AC:

AN:

40736

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24340

East Asian (EAS)

AF:

0.00

AC:

AN:

38098

South Asian (SAS)

AF:

0.00

AC:

AN:

80046

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5628

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1089894

Other (OTH)

AF:

0.00

AC:

AN:

58604

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

AF:

0.0000131

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74372

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000482

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Oct 06, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S22N variant (also known as c.65G>A), located in coding exon 2 of the CACNA1C gene, results from a G to A substitution at nucleotide position 65. The serine at codon 22 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Long QT syndrome

Benign:1

Feb 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

CardioboostArm

Benign

0.0000021

BayesDel_addAF

Uncertain

0.072

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.012

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

Eigen

Benign

-0.087

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.95

M_CAP

Benign

0.019

MetaRNN

Benign

0.24

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

0.50

MutationAssessor

Benign

1.1

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

PhyloP100

6.3

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.4

N;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

0.35

Sift

Benign

0.074

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

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

0.0, 0.61, 0.0010, 0.78

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

Vest4

0.56, 0.61, 0.59, 0.61, 0.59, 0.59, 0.60, 0.60, 0.60, 0.64, 0.60, 0.57, 0.60, 0.58, 0.60, 0.63, 0.61, 0.60

MutPred

0.22

.;Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);Gain of catalytic residue at Y20 (P = 0);

MVP

0.79

MPC

0.99

ClinPred

0.65

GERP RS

5.8

PromoterAI

0.016

Neutral

(source)

gMVP

0.53

Mutation Taster

=63/37

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