12-2566522-A-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM5PP3_Moderate

The NM_000719.7(CACNA1C):c.1609A>T(p.Asn537Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N537D) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Uncertain_significance. The variant received 4 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.1609A>T	p.Asn537Tyr	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>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.1699A>T	p.Asn567Tyr	missense_variant	Exon 12 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.1774A>T	p.Asn592Tyr	missense_variant	Exon 13 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.1699A>T	p.Asn567Tyr	missense_variant	Exon 12 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.1699A>T	p.Asn567Tyr	missense_variant	Exon 12 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.1699A>T	p.Asn567Tyr	missense_variant	Exon 12 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.1699A>T	p.Asn567Tyr	missense_variant	Exon 12 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.1684A>T	p.Asn562Tyr	missense_variant	Exon 13 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.1684A>T	p.Asn562Tyr	missense_variant	Exon 13 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.1600A>T	p.Asn534Tyr	missense_variant	Exon 12 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.1609A>T	p.Asn537Tyr	missense_variant	Exon 12 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*216A>T		non_coding_transcript_exon_variant	Exon 10 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*216A>T		3_prime_UTR_variant	Exon 10 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152106

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

218104

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000208

AC:

AN:

1442292

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715392

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33034

American (AMR)

AF:

0.0000473

AC:

AN:

42272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25738

East Asian (EAS)

AF:

0.00

AC:

AN:

38590

South Asian (SAS)

AF:

0.00

AC:

AN:

82454

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51952

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1102792

Other (OTH)

AF:

0.00

AC:

AN:

59722

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.242

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

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74306

African (AFR)

AF:

0.00

AC:

AN:

41420

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

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:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2092

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

CardioboostArm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.89

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

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.93

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

Benign

0.0

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

PhyloP100

9.3

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-7.1

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

0.87

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

Vest4

0.93

ClinPred

1.0

GERP RS

2.8

PromoterAI

-0.027

Neutral

(source)

gMVP

1.0

Mutation Taster

=21/79

disease causing

(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

Computational scores

Splicing

Publications

Other links and lift over