12-2668958-T-C

Variant names:

• chr12-2668958-T-C
• NM_000719.7:c.4649T>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000719.7(CACNA1C):​c.4649T>C​(p.Leu1550Pro) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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-AS2 (HGNC:):

CACNA1C-AS2 (HGNC:40118): (CACNA1C antisense RNA 2)

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• 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, 0.934

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4649T>C	p.Leu1550Pro	missense_variant	Exon 38 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4649T>C	p.Leu1550Pro	missense_variant	Exon 38 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4649T>C	p.Leu1550Pro	missense_variant	Exon 38 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4649T>C	p.Leu1550Pro	missense_variant	Exon 38 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4883T>C	p.Leu1628Pro	missense_variant	Exon 40 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4649T>C	p.Leu1550Pro	missense_variant	Exon 38 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4616T>C	p.Leu1539Pro	missense_variant	Exon 37 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4814T>C	p.Leu1605Pro	missense_variant	Exon 39 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4793T>C	p.Leu1598Pro	missense_variant	Exon 40 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4715T>C	p.Leu1572Pro	missense_variant	Exon 38 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4649T>C	p.Leu1550Pro	missense_variant	Exon 38 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4649T>C	p.Leu1550Pro	missense_variant	Exon 38 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4739T>C	p.Leu1580Pro	missense_variant	Exon 38 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4739T>C	p.Leu1580Pro	missense_variant	Exon 38 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4739T>C	p.Leu1580Pro	missense_variant	Exon 38 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4739T>C	p.Leu1580Pro	missense_variant	Exon 38 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4733T>C	p.Leu1578Pro	missense_variant	Exon 39 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4724T>C	p.Leu1575Pro	missense_variant	Exon 39 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4709T>C	p.Leu1570Pro	missense_variant	Exon 39 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4649T>C	p.Leu1550Pro	missense_variant	Exon 38 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4649T>C	p.Leu1550Pro	missense_variant	Exon 38 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4649T>C	p.Leu1550Pro	missense_variant	Exon 38 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4700T>C	p.Leu1567Pro	missense_variant	Exon 38 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4691T>C	p.Leu1564Pro	missense_variant	Exon 38 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4616T>C	p.Leu1539Pro	missense_variant	Exon 37 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4616T>C	p.Leu1539Pro	missense_variant	Exon 37 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4610T>C	p.Leu1537Pro	missense_variant	Exon 37 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4649T>C	p.Leu1550Pro	missense_variant	Exon 38 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4649T>C	p.Leu1550Pro	missense_variant	Exon 38 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4649T>C	p.Leu1550Pro	missense_variant	Exon 38 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4649T>C	p.Leu1550Pro	missense_variant	Exon 38 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4649T>C	p.Leu1550Pro	missense_variant	Exon 38 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4640T>C	p.Leu1547Pro	missense_variant	Exon 38 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4616T>C	p.Leu1539Pro	missense_variant	Exon 37 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 03, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.96	D
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	D
MutationAssessor	Pathogenic	3.1	.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.5	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.96
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;.
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, 0.99	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D;.
Vest4		0.98
MutPred		0.62		.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at N1595 (P = 0.0011);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.99
MPC		2.8
ClinPred		1.0	D
GERP RS		3.7
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-2778124;