12-2556956-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3

The NM_000719.7(CACNA1C):c.1487G>T(p.Arg496Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.00

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 Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 122) in uniprot entity CAC1C_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000719.7

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.745

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 47	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 47	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.1577G>T	p.Arg526Leu	missense_variant	Exon 11 of 50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 48	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 47	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.1652G>T	p.Arg551Leu	missense_variant	Exon 12 of 48			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 48	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.1577G>T	p.Arg526Leu	missense_variant	Exon 11 of 47			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.1577G>T	p.Arg526Leu	missense_variant	Exon 11 of 47			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.1577G>T	p.Arg526Leu	missense_variant	Exon 11 of 47			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.1577G>T	p.Arg526Leu	missense_variant	Exon 11 of 47			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.1562G>T	p.Arg521Leu	missense_variant	Exon 12 of 48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.1562G>T	p.Arg521Leu	missense_variant	Exon 12 of 47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 47	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 47			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.1478G>T	p.Arg493Leu	missense_variant	Exon 11 of 47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.1487G>T	p.Arg496Leu	missense_variant	Exon 11 of 46			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000480911.6 link	n.*94G>T		non_coding_transcript_exon_variant	Exon 9 of 27	5		ENSP00000437936.2	F5H638
CACNA1C	ENST00000480911.6 link	n.*94G>T		3_prime_UTR_variant	Exon 9 of 27	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460506

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726644

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

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

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.74

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

MetaSVM

Uncertain

0.74

MutationAssessor

Uncertain

2.1

.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;.;.

PrimateAI

Pathogenic

0.92

PROVEAN

Uncertain

-2.5

N;N;D;N;N;D;N;N;N;N;N;D;N;N;N;N;N;N;N;N;D;N;D

REVEL

Pathogenic

0.68

Sift

Benign

0.13

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

0.17

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

Polyphen

0.43, 0.11, 0.0010, 0.23, 0.63, 0.085, 0.59, 0.96, 1.0, 0.86, 0.15

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

Vest4

0.87

MutPred

0.57

.;Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);Gain of catalytic residue at K499 (P = 0.0046);

MVP

0.98

MPC

1.3

ClinPred

0.95

GERP RS

5.0

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over