12-2504932-G-C

Position:

• chr12-2504932-G-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_000719.7(CACNA1C):​c.1204G>C​(p.Gly402Arg) 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. 12/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G402S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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 11 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 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, 0.967

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1204G>C	p.Gly402Arg	missense_variant	8/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1217+393G>C		intron_variant		ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399655.6	c.1204G>C	p.Gly402Arg	missense_variant	8/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1294G>C	p.Gly432Arg	missense_variant	8/50			ENSP00000507184.1
CACNA1C	ENST00000347598.9	c.1204G>C	p.Gly402Arg	missense_variant	8/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1204G>C	p.Gly402Arg	missense_variant	8/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1204G>C	p.Gly402Arg	missense_variant	8/48	1		ENSP00000329877.7
CACNA1C	ENST00000399638.5	c.1204G>C	p.Gly402Arg	missense_variant	8/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1204G>C	p.Gly402Arg	missense_variant	8/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1204G>C	p.Gly402Arg	missense_variant	8/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1204G>C	p.Gly402Arg	missense_variant	8/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1204G>C	p.Gly402Arg	missense_variant	8/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1204G>C	p.Gly402Arg	missense_variant	8/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1204G>C	p.Gly402Arg	missense_variant	8/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1204G>C	p.Gly402Arg	missense_variant	8/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1204G>C	p.Gly402Arg	missense_variant	8/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1204G>C	p.Gly402Arg	missense_variant	8/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1204G>C	p.Gly402Arg	missense_variant	8/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1204G>C	p.Gly402Arg	missense_variant	8/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1204G>C	p.Gly402Arg	missense_variant	8/47	1		ENSP00000382510.1
CACNA1C	ENST00000399644.5	c.1204G>C	p.Gly402Arg	missense_variant	8/47	1		ENSP00000382552.1
CACNA1C	ENST00000683482.1	c.1195G>C	p.Gly399Arg	missense_variant	8/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1204G>C	p.Gly402Arg	missense_variant	8/46			ENSP00000507309.1
CACNA1C	ENST00000399603.6	c.1217+393G>C		intron_variant		5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000406454.8	c.1217+393G>C		intron_variant		5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1217+393G>C		intron_variant		5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1307+393G>C		intron_variant				ENSP00000507867.1
CACNA1C	ENST00000399617.6	c.1217+393G>C		intron_variant		5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1307+393G>C		intron_variant				ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1307+393G>C		intron_variant				ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1307+393G>C		intron_variant				ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1307+393G>C		intron_variant				ENSP00000506882.1
CACNA1C	ENST00000399641.6	c.1217+393G>C		intron_variant		1		ENSP00000382549.1
CACNA1C	ENST00000682835.1	c.1217+393G>C		intron_variant				ENSP00000507282.1
CACNA1C	ENST00000480911.6	n.1113+11546G>C		intron_variant		5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.97	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	4.3	.;H;.;H;H;H;H;H;H;H;H;H;H;H;H;.;H;H
PrimateAI	Pathogenic	0.97	D
PROVEAN	Pathogenic	-7.2	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	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
Polyphen		1.0	.;D;.;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D
Vest4		0.95
MutPred		0.79		Gain of catalytic residue at N398 (P = 0.0107);Gain of catalytic residue at N398 (P = 0.0107);Gain of catalytic residue at N398 (P = 0.0107);Gain of catalytic residue at N398 (P = 0.0107);Gain of catalytic residue at N398 (P = 0.0107);Gain of catalytic residue at N398 (P = 0.0107);Gain of catalytic residue at N398 (P = 0.0107);Gain of catalytic residue at N398 (P = 0.0107);Gain of catalytic residue at N398 (P = 0.0107);Gain of catalytic residue at N398 (P = 0.0107);Gain of catalytic residue at N398 (P = 0.0107);Gain of catalytic residue at N398 (P = 0.0107);Gain of catalytic residue at N398 (P = 0.0107);Gain of catalytic residue at N398 (P = 0.0107);Gain of catalytic residue at N398 (P = 0.0107);Gain of catalytic residue at N398 (P = 0.0107);Gain of catalytic residue at N398 (P = 0.0107);Gain of catalytic residue at N398 (P = 0.0107);
MVP		0.99
MPC		2.4
ClinPred		1.0	D
GERP RS		5.3
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

Other links and lift over

dbSNP: rs80315385; hg19: chr12-2614098;