chr12-2566465-C-A

Variant names:

• chr12-2566465-C-A
• NM_000719.7:c.1552C>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_000719.7(CACNA1C):​c.1552C>A​(p.Arg518Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R518C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.17

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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, 0.912
• PP5: Variant 12-2566465-C-A is Pathogenic according to our data. Variant chr12-2566465-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3233417.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr12-2566465-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1642C>A	p.Arg548Ser	missense_variant	Exon 12 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1717C>A	p.Arg573Ser	missense_variant	Exon 13 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1642C>A	p.Arg548Ser	missense_variant	Exon 12 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1642C>A	p.Arg548Ser	missense_variant	Exon 12 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1642C>A	p.Arg548Ser	missense_variant	Exon 12 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1642C>A	p.Arg548Ser	missense_variant	Exon 12 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1627C>A	p.Arg543Ser	missense_variant	Exon 13 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1627C>A	p.Arg543Ser	missense_variant	Exon 13 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1543C>A	p.Arg515Ser	missense_variant	Exon 12 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1552C>A	p.Arg518Ser	missense_variant	Exon 12 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*159C>A		non_coding_transcript_exon_variant	Exon 10 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*159C>A		3_prime_UTR_variant	Exon 10 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1443586 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Long QT syndrome;C1832916:Timothy syndrome Pathogenic:1

Apr 29, 2024

Curation Department, Healx

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Following evidence codes supports Likely Pathogenic classification: PM2,PM5,PM6,PP3,PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.91	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	D
MutationAssessor	Pathogenic	4.2	.;H;.;H;H;H;H;H;H;H;H;H;H;H;H;H;.;H;H;H;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.7	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	0.90
Sift	Uncertain	0.0040	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	0.0010	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, 1.0, 0.99, 1.0	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.83
MutPred		0.60		.;Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);Gain of catalytic residue at K522 (P = 0);
MVP		0.98
MPC		2.4
ClinPred		0.99	D
GERP RS		4.4
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-2675631;