12-2682591-A-G

Position:

• chr12-2682591-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_000719.7(CACNA1C):​c.5486A>G​(p.Glu1829Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000744 in 1,612,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.50

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 Likely_benign. Variant got -4 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29681242).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5486A>G	p.Glu1829Gly	missense_variant	43/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5486A>G	p.Glu1829Gly	missense_variant	43/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5486A>G	p.Glu1829Gly	missense_variant	43/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5486A>G	p.Glu1829Gly	missense_variant	43/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5825A>G	p.Glu1942Gly	missense_variant	46/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5699A>G	p.Glu1900Gly	missense_variant	44/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5666A>G	p.Glu1889Gly	missense_variant	43/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5651A>G	p.Glu1884Gly	missense_variant	44/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5630A>G	p.Glu1877Gly	missense_variant	45/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5609A>G	p.Glu1870Gly	missense_variant	43/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5591A>G	p.Glu1864Gly	missense_variant	44/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5591A>G	p.Glu1864Gly	missense_variant	44/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5576A>G	p.Glu1859Gly	missense_variant	43/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5576A>G	p.Glu1859Gly	missense_variant	43/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5576A>G	p.Glu1859Gly	missense_variant	43/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5576A>G	p.Glu1859Gly	missense_variant	43/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5570A>G	p.Glu1857Gly	missense_variant	44/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5561A>G	p.Glu1854Gly	missense_variant	44/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5546A>G	p.Glu1849Gly	missense_variant	44/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5543A>G	p.Glu1848Gly	missense_variant	43/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5543A>G	p.Glu1848Gly	missense_variant	43/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5543A>G	p.Glu1848Gly	missense_variant	43/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5537A>G	p.Glu1846Gly	missense_variant	43/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5528A>G	p.Glu1843Gly	missense_variant	43/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5510A>G	p.Glu1837Gly	missense_variant	42/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5510A>G	p.Glu1837Gly	missense_variant	42/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5504A>G	p.Glu1835Gly	missense_variant	42/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5486A>G	p.Glu1829Gly	missense_variant	43/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5486A>G	p.Glu1829Gly	missense_variant	43/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5486A>G	p.Glu1829Gly	missense_variant	43/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5486A>G	p.Glu1829Gly	missense_variant	43/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5486A>G	p.Glu1829Gly	missense_variant	43/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5477A>G	p.Glu1826Gly	missense_variant	43/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5453A>G	p.Glu1818Gly	missense_variant	42/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152056 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 AF: 0.00000753 AC: 11 AN: 1460356 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726382

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152056 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74246

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

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 13, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1829 of the CACNA1C protein (p.Glu1829Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of long QT syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 526936). 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. 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2020

The p.E1829G variant (also known as c.5486A>G), located in coding exon 43 of the CACNA1C gene, results from an A to G substitution at nucleotide position 5486. The glutamic acid at codon 1829 is replaced by glycine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species; however, glycine is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.84	D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.3	N;N;D;N;N;N;N;N;D;N;N;N;N;N;N;N;D;N;N;N;N;N;.
REVEL	Uncertain	0.32
Sift	Benign	0.083	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;D;.
Sift4G	Benign	0.097	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.0010, 0.23	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4		0.27
MVP		0.55
MPC		0.22
ClinPred		0.50	T
GERP RS		4.8
gMVP		0.60

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: rs1350126839; hg19: chr12-2791757;