chr12-2566522-A-T

Position:

chr12-2566522-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM5PP2PP3_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. 11/19 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

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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 id is 521136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ 6.4654 (greater than the threshold 3.09). Trascript score misZ 7.2674 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7 linkuse as main transcript	c.1609A>T	p.Asn537Tyr	missense_variant	12/47	ENST00000399655.6
CACNA1C	NM_001167623.2 linkuse as main transcript	c.1609A>T	p.Asn537Tyr	missense_variant	12/47	ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6 linkuse as main transcript	c.1609A>T	p.Asn537Tyr	missense_variant	12/47	5	NM_001167623.2		Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.1609A>T	p.Asn537Tyr	missense_variant	12/47	1	NM_000719.7		Q13936-12

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152106

Hom.:

Cov.:

FAILED QC

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

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000473

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.07e-7

Gnomad4 OTH exome

AF:

0.00

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

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

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

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

Pathogenic

4.2

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

MutationTaster

Benign

1.0

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

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

Polyphen

1.0, 1.0

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

Vest4

0.93

MutPred

0.50

.;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

0.97

MPC

2.5

ClinPred

1.0

GERP RS

2.8

gMVP

1.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over