rs535608443

Variant names:

• chr12-2115272-A-C
• NM_000719.7:c.98A>C

Your query was ambiguous. Multiple possible variants found:

• chr12-2115272-A-C
• chr12-2115272-A-G
• chr12-2115272-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000719.7(CACNA1C):​c.98A>C​(p.Asn33Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.58

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.188A>C	p.Asn63Thr	missense_variant	Exon 2 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.188A>C	p.Asn63Thr	missense_variant	Exon 2 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.188A>C	p.Asn63Thr	missense_variant	Exon 2 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.188A>C	p.Asn63Thr	missense_variant	Exon 2 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.188A>C	p.Asn63Thr	missense_variant	Exon 2 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.188A>C	p.Asn63Thr	missense_variant	Exon 2 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.98A>C	p.Asn33Thr	missense_variant	Exon 2 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.47A>C	p.Asn16Thr	missense_variant	Exon 1 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.98A>C		non_coding_transcript_exon_variant	Exon 2 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Dec 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 33 of the CACNA1C protein (p.Asn33Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 95%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.092	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.027	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	-0.0066
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.085	D
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	0.69	.;.;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;.;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.3	D;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.073	T;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;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.56, 0.55, 0.0010, 0.93, 0.99, 0.84	.;.;P;.;P;P;B;P;P;P;P;P;P;P;P;D;P;.;P;P;.;.;.;.
Vest4		0.39, 0.37, 0.35, 0.37, 0.35, 0.37, 0.36, 0.39, 0.35, 0.37, 0.37, 0.33, 0.36, 0.41, 0.38, 0.40, 0.37
MutPred		0.44		.;Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);Gain of catalytic residue at M30 (P = 0.0018);
MVP		0.88
MPC		1.1
ClinPred		0.77	D
GERP RS		5.8
gMVP		0.58

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: chr12-2224438;