rs1060503443

Variant names:

• chr12-2581646-T-A
• rs1060503443
• NM_000719.7:c.1952T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000719.7(CACNA1C):​c.1952T>A​(p.Ile651Asn) 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. 14/22 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. I651V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 29)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.97
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000719.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2042T>A	p.Ile681Asn	missense_variant	Exon 14 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2117T>A	p.Ile706Asn	missense_variant	Exon 15 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2042T>A	p.Ile681Asn	missense_variant	Exon 14 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2042T>A	p.Ile681Asn	missense_variant	Exon 14 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2042T>A	p.Ile681Asn	missense_variant	Exon 14 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2042T>A	p.Ile681Asn	missense_variant	Exon 14 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2027T>A	p.Ile676Asn	missense_variant	Exon 15 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2027T>A	p.Ile676Asn	missense_variant	Exon 15 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1943T>A	p.Ile648Asn	missense_variant	Exon 14 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1952T>A	p.Ile651Asn	missense_variant	Exon 14 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*559T>A		non_coding_transcript_exon_variant	Exon 12 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*559T>A		3_prime_UTR_variant	Exon 12 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Nov 12, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine with asparagine at codon 651 of the CACNA1C protein (p.Ile651Asn). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and asparagine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CACNA1C-related disease. 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: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.96	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	1.0	D
MutationAssessor	Pathogenic	4.5	.;H;.;H;H;H;H;H;H;H;H;H;H;H;H;H;.;H;H;H;.;.;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.6	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
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;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		0.99, 0.99, 1.0, 0.99, 0.97, 1.0, 0.94, 0.99, 0.89	.;D;D;D;D;D;D;D;D;D;D;P;D;D;D;D;.;D;D;.;.;.;P
Vest4		0.91
MutPred		0.79		.;Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);Gain of disorder (P = 0.0199);
MVP		0.97
MPC		2.9
ClinPred		1.0	D
GERP RS		4.4
gMVP		1.0
Mutation Taster		=22/78	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: rs1060503443; hg19: chr12-2690812;