rs878854141

Variant names:

• chr12-2607121-G-A
• rs878854141
• NM_000719.7:c.3347G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2607121-G-A
• chr12-2607121-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_000719.7(CACNA1C):​c.3347G>A​(p.Gly1116Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

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-AS3 (HGNC:40117): (CACNA1C antisense RNA 3)

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a region_of_interest Dihydropyridine binding (size 89) in uniprot entity CAC1C_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000719.7
• 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, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3497G>A	p.Gly1166Glu	missense_variant	Exon 27 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3512G>A	p.Gly1171Glu	missense_variant	Exon 27 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3407G>A	p.Gly1136Glu	missense_variant	Exon 27 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3437G>A	p.Gly1146Glu	missense_variant	Exon 26 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3437G>A	p.Gly1146Glu	missense_variant	Exon 26 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3437G>A	p.Gly1146Glu	missense_variant	Exon 26 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3437G>A	p.Gly1146Glu	missense_variant	Exon 26 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3422G>A	p.Gly1141Glu	missense_variant	Exon 27 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3407G>A	p.Gly1136Glu	missense_variant	Exon 27 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3422G>A	p.Gly1141Glu	missense_variant	Exon 27 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3338G>A	p.Gly1113Glu	missense_variant	Exon 26 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3347G>A	p.Gly1116Glu	missense_variant	Exon 26 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1954G>A		non_coding_transcript_exon_variant	Exon 24 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1954G>A		3_prime_UTR_variant	Exon 24 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Mar 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1116 of the CACNA1C protein (p.Gly1116Glu). This variant is present in population databases (no rsID available, gnomAD 0.007%). 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 expected to disrupt CACNA1C protein function with a positive 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	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.94	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	0.89	D
MutationAssessor	Pathogenic	4.4	.;.;.;.;.;.;.;.;.;.;.;H;H;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.6	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	0.94
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	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 0.99	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.86
MutPred		0.74		.;.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at W1137 (P = 0.0026);Gain of catalytic residue at W1137 (P = 0.0026);.;.;.;.;.;.;.;.;.;.;
MVP		0.96
MPC		2.5
ClinPred		1.0	D
GERP RS		4.0
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs878854141; hg19: chr12-2716287;