rs1467561684

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_000719.7(CACNA1C):c.1609A>G(p.Asn537Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. N537N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 9.32

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: Pathogenic. The variant received 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.923

PP5

Variant 12-2566522-A-G is Pathogenic according to our data. Variant chr12-2566522-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 521136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.1609A>G	p.Asn537Asp	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.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.1699A>G	p.Asn567Asp	missense_variant	Exon 12 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.1774A>G	p.Asn592Asp	missense_variant	Exon 13 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.1699A>G	p.Asn567Asp	missense_variant	Exon 12 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.1699A>G	p.Asn567Asp	missense_variant	Exon 12 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.1699A>G	p.Asn567Asp	missense_variant	Exon 12 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.1699A>G	p.Asn567Asp	missense_variant	Exon 12 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.1684A>G	p.Asn562Asp	missense_variant	Exon 13 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.1684A>G	p.Asn562Asp	missense_variant	Exon 13 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.1600A>G	p.Asn534Asp	missense_variant	Exon 12 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.1609A>G	p.Asn537Asp	missense_variant	Exon 12 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*216A>G		non_coding_transcript_exon_variant	Exon 10 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*216A>G		3_prime_UTR_variant	Exon 10 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Timothy syndrome

Pathogenic:1

Feb 23, 2023

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. The variant has been reported as assumed (i.e. paternity and maternity not confirmed) de novo by an outside laboratory. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.82). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CACNA1C related disorder (ClinVar ID: VCV000521136). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Cardiovascular phenotype

Pathogenic:1

Jul 25, 2023

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1609A>G (p.N537D) alteration is located in exon 12 (coding exon 12) of the CACNA1C gene. This alteration results from an A to G substitution at nucleotide position 1609, causing the asparagine (N) at amino acid position 537 to be replaced by an aspartic acid (D)._x000D_ _x000D_ Based on the available evidence, the CACNA1C c.1609A>G (p.N537D) alteration is classified as likely pathogenic for CACNA1C-related neurodevelopmental disorder; however, its clinical significance for Timothy syndrome and CACNA1C-related long QT syndrome is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). The L-type Cav1.2 channel (encoded by CACNA1C) consists of four homologous domains, each containing six transmembrane segments S1-S6. Segments S1-S4 form the voltage-sensing domain. The p.N537 amino acid is located in transmembrane segment S1 of domain II. Structural modeling performed in house at Ambry Genetics suggests that the p.N537 amino acid is essential for Cav1.2 function as a voltage-dependent calcium channel. The p.N537D alteration may affect the gating of the Cav1.2 channel and transform the channel into a proton channel (Ramsey, 2010; Musset, 2011). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

CardioboostArm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

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

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

.;H;.;H;H;H;H;H;H;H;H;H;H;H;H;H;.;H;H;H;.;.;.

PhyloP100

9.3

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-4.5

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0, 0.99, 1.0, 1.0, 1.0

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

Vest4

0.95

MutPred

0.57

.;Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);Gain of catalytic residue at F535 (P = 0.0017);

MVP

0.98

MPC

2.4

ClinPred

1.0

GERP RS

2.8

PromoterAI

-0.0042

Neutral

(source)

gMVP

1.0

Mutation Taster

=53/47

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

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