rs781306162

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_000719.7(CACNA1C):c.1649A>G(p.Asn550Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000388 in 1,598,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N550K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.25

Publications

3 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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1659621).

BP6

Variant 12-2566562-A-G is Benign according to our data. Variant chr12-2566562-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 575658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.1739A>G	p.Asn580Ser	missense_variant	Exon 12 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.1814A>G	p.Asn605Ser	missense_variant	Exon 13 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.1739A>G	p.Asn580Ser	missense_variant	Exon 12 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.1739A>G	p.Asn580Ser	missense_variant	Exon 12 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.1739A>G	p.Asn580Ser	missense_variant	Exon 12 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.1739A>G	p.Asn580Ser	missense_variant	Exon 12 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.1724A>G	p.Asn575Ser	missense_variant	Exon 13 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.1724A>G	p.Asn575Ser	missense_variant	Exon 13 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.1640A>G	p.Asn547Ser	missense_variant	Exon 12 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.1649A>G	p.Asn550Ser	missense_variant	Exon 12 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*256A>G		non_coding_transcript_exon_variant	Exon 10 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*256A>G		3_prime_UTR_variant	Exon 10 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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

GnomAD2 exomes

AF:

0.0000178

AC:

AN:

224750

AF XY:

0.0000165

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000618

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000610

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000990

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000408

AC:

AN:

1446438

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

717842

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33058

American (AMR)

AF:

0.0000232

AC:

AN:

43144

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25796

East Asian (EAS)

AF:

0.00

AC:

AN:

38808

South Asian (SAS)

AF:

0.00

AC:

AN:

82940

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5618

European-Non Finnish (NFE)

AF:

0.0000498

AC:

AN:

1104870

Other (OTH)

AF:

0.0000334

AC:

AN:

59836

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41430

American (AMR)

AF:

0.0000655

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000740

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Benign:1

Jul 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Sep 08, 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

0.089

CardioboostArm

Benign

0.000071

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.37

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

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.011

FATHMM_MKL

Pathogenic

0.98

M_CAP

Benign

0.070

MetaRNN

Benign

0.17

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

-0.17

MutationAssessor

Benign

0.43

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

PhyloP100

4.3

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.88

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

0.33

Sift

Benign

0.48

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

Sift4G

Benign

0.53

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, 0.0010, 0.018

.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B

Vest4

0.14

MutPred

0.35

.;Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);

MVP

0.70

MPC

0.85

ClinPred

0.13

GERP RS

4.8

PromoterAI

-0.063

Neutral

(source)

gMVP

0.42

Mutation Taster

=85/15

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