rs201861473

Positions:

• chr12-2679587-C-A
• chr12-2679587-C-G
• chr12-2679587-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000719.7(CACNA1C):​c.5235C>A​(p.His1745Gln) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.384

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.784

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5235C>A	p.His1745Gln	missense_variant	42/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5235C>A	p.His1745Gln	missense_variant	42/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5235C>A	p.His1745Gln	missense_variant	42/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5235C>A	p.His1745Gln	missense_variant	42/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5469C>A	p.His1823Gln	missense_variant	44/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5235C>A	p.His1745Gln	missense_variant	42/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5202C>A	p.His1734Gln	missense_variant	41/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5400C>A	p.His1800Gln	missense_variant	43/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5379C>A	p.His1793Gln	missense_variant	44/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5358C>A	p.His1786Gln	missense_variant	42/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5235C>A	p.His1745Gln	missense_variant	42/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5235C>A	p.His1745Gln	missense_variant	42/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5325C>A	p.His1775Gln	missense_variant	42/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5325C>A	p.His1775Gln	missense_variant	42/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5325C>A	p.His1775Gln	missense_variant	42/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5325C>A	p.His1775Gln	missense_variant	42/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5319C>A	p.His1773Gln	missense_variant	43/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5310C>A	p.His1770Gln	missense_variant	43/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5295C>A	p.His1765Gln	missense_variant	43/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5292C>A	p.His1764Gln	missense_variant	42/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5292C>A	p.His1764Gln	missense_variant	42/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5292C>A	p.His1764Gln	missense_variant	42/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5286C>A	p.His1762Gln	missense_variant	42/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5277C>A	p.His1759Gln	missense_variant	42/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5259C>A	p.His1753Gln	missense_variant	41/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5259C>A	p.His1753Gln	missense_variant	41/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5253C>A	p.His1751Gln	missense_variant	41/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5235C>A	p.His1745Gln	missense_variant	42/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5235C>A	p.His1745Gln	missense_variant	42/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5235C>A	p.His1745Gln	missense_variant	42/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5235C>A	p.His1745Gln	missense_variant	42/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5235C>A	p.His1745Gln	missense_variant	42/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5226C>A	p.His1742Gln	missense_variant	42/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5202C>A	p.His1734Gln	missense_variant	41/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.023
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.65	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.78	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	0.43	D
MutationAssessor	Uncertain	2.5	.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Uncertain	0.57
Sift	Benign	0.052	T;T;D;T;D;T;D;T;T;T;D;D;T;D;T;D;D;D;D;D;D;D;.
Sift4G	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.99, 0.0090, 0.80, 0.65, 1.0, 0.010, 1.0, 0.81	.;D;B;P;P;D;D;D;B;D;D;D;D;P;D;.;D;D;.;.;.;D;.
Vest4		0.67
MutPred		0.18		.;.;.;.;.;.;.;.;.;.;Gain of glycosylation at P1791 (P = 0.1319);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.97
MPC		0.24
ClinPred		0.93	D
GERP RS		1.5
gMVP		0.34

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: rs201861473; hg19: chr12-2788753;