12-2664961-A-T

Position:

• chr12-2664961-A-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.4369A>T​(p.Ile1457Phe) variant causes a missense change. 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.83

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, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4369A>T	p.Ile1457Phe	missense_variant	35/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4369A>T	p.Ile1457Phe	missense_variant	35/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4369A>T	p.Ile1457Phe	missense_variant	35/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4369A>T	p.Ile1457Phe	missense_variant	35/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4603A>T	p.Ile1535Phe	missense_variant	37/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4369A>T	p.Ile1457Phe	missense_variant	35/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4336A>T	p.Ile1446Phe	missense_variant	34/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4534A>T	p.Ile1512Phe	missense_variant	36/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4513A>T	p.Ile1505Phe	missense_variant	37/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4435A>T	p.Ile1479Phe	missense_variant	35/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4369A>T	p.Ile1457Phe	missense_variant	35/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4369A>T	p.Ile1457Phe	missense_variant	35/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4459A>T	p.Ile1487Phe	missense_variant	35/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4459A>T	p.Ile1487Phe	missense_variant	35/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4459A>T	p.Ile1487Phe	missense_variant	35/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4459A>T	p.Ile1487Phe	missense_variant	35/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4453A>T	p.Ile1485Phe	missense_variant	36/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4444A>T	p.Ile1482Phe	missense_variant	36/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4429A>T	p.Ile1477Phe	missense_variant	36/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4369A>T	p.Ile1457Phe	missense_variant	35/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4369A>T	p.Ile1457Phe	missense_variant	35/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4369A>T	p.Ile1457Phe	missense_variant	35/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4420A>T	p.Ile1474Phe	missense_variant	35/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4411A>T	p.Ile1471Phe	missense_variant	35/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4336A>T	p.Ile1446Phe	missense_variant	34/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4336A>T	p.Ile1446Phe	missense_variant	34/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4330A>T	p.Ile1444Phe	missense_variant	34/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4369A>T	p.Ile1457Phe	missense_variant	35/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4369A>T	p.Ile1457Phe	missense_variant	35/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4369A>T	p.Ile1457Phe	missense_variant	35/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4369A>T	p.Ile1457Phe	missense_variant	35/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4369A>T	p.Ile1457Phe	missense_variant	35/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4360A>T	p.Ile1454Phe	missense_variant	35/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4336A>T	p.Ile1446Phe	missense_variant	34/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Skane University Hospital Lund

May 27, 2022

- -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2018

This variant has not been reported in the literature in individuals with CACNA1C-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with phenylalanine at codon 1457 of the CACNA1C protein (p.Ile1457Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.58	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	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.88
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	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.97, 0.99, 0.99, 0.95, 0.97, 0.91, 0.99, 0.96	.;D;D;D;D;D;P;P;D;D;P;P;P;D;P;.;P;P;.;.;.;D;.
Vest4		0.63
MutPred		0.60		.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at S1506 (P = 0);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.84
MPC		2.3
ClinPred		0.99	D
GERP RS		4.4
gMVP		0.95

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: rs781315664; hg19: chr12-2774127;