12-2664961-A-T

Variant names:

• chr12-2664961-A-T
• rs781315664
• NM_000719.7:c.4369A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1457T) has been classified 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
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Timothy syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• long QT syndrome 8

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
• Brugada syndrome 3

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• short QT syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

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

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Uncertain:1

Jan 29, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 has not been reported in the literature in individuals with CACNA1C-related disease. 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
AlphaMissense	Pathogenic	0.59
CardioboostArm	Benign	0.011
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;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		4.8
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
Mutation Taster		=47/53	disease causing

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

Other links and lift over

dbSNP: rs781315664; hg19: chr12-2774127;