chr12-2682608-G-A

Position:

• chr12-2682608-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_000719.7(CACNA1C):​c.5503G>A​(p.Glu1835Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000037 in 1,460,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.29

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 -5 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=0.13992766).
• BS2: High AC in GnomAdExome4 at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5503G>A	p.Glu1835Lys	missense_variant	43/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5503G>A	p.Glu1835Lys	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.5503G>A	p.Glu1835Lys	missense_variant	43/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5503G>A	p.Glu1835Lys	missense_variant	43/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5842G>A	p.Glu1948Lys	missense_variant	46/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5716G>A	p.Glu1906Lys	missense_variant	44/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5683G>A	p.Glu1895Lys	missense_variant	43/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5668G>A	p.Glu1890Lys	missense_variant	44/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5647G>A	p.Glu1883Lys	missense_variant	45/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5626G>A	p.Glu1876Lys	missense_variant	43/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5608G>A	p.Glu1870Lys	missense_variant	44/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5608G>A	p.Glu1870Lys	missense_variant	44/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5593G>A	p.Glu1865Lys	missense_variant	43/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5593G>A	p.Glu1865Lys	missense_variant	43/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5593G>A	p.Glu1865Lys	missense_variant	43/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5593G>A	p.Glu1865Lys	missense_variant	43/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5587G>A	p.Glu1863Lys	missense_variant	44/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5578G>A	p.Glu1860Lys	missense_variant	44/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5563G>A	p.Glu1855Lys	missense_variant	44/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5560G>A	p.Glu1854Lys	missense_variant	43/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5560G>A	p.Glu1854Lys	missense_variant	43/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5560G>A	p.Glu1854Lys	missense_variant	43/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5554G>A	p.Glu1852Lys	missense_variant	43/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5545G>A	p.Glu1849Lys	missense_variant	43/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5527G>A	p.Glu1843Lys	missense_variant	42/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5527G>A	p.Glu1843Lys	missense_variant	42/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5521G>A	p.Glu1841Lys	missense_variant	42/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5503G>A	p.Glu1835Lys	missense_variant	43/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5503G>A	p.Glu1835Lys	missense_variant	43/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5503G>A	p.Glu1835Lys	missense_variant	43/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5503G>A	p.Glu1835Lys	missense_variant	43/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5503G>A	p.Glu1835Lys	missense_variant	43/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5494G>A	p.Glu1832Lys	missense_variant	43/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5470G>A	p.Glu1824Lys	missense_variant	42/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247296 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134172

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000370 AC: 54 AN: 1460440 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26 AN XY: 726398

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

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: 0.0000468

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Jan 08, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 411721). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1835 of the CACNA1C protein (p.Glu1835Lys). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 12, 2020

The p.E1835K variant (also known as c.5503G>A), located in coding exon 43 of the CACNA1C gene, results from a G to A substitution at nucleotide position 5503. The glutamic acid at codon 1835 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available 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	Benign	-0.0054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	17
DANN	Benign	0.77
DEOGEN2	Benign	0.012	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.88
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.14	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	-0.00050	T
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.31
Sift	Benign	0.083	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;T;T;T;D;T;.
Sift4G	Benign	0.32	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	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4		0.21
MVP		0.69
MPC		0.21
ClinPred		0.10	T
GERP RS		0.91
gMVP		0.62

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

LitVar

Other links and lift over

dbSNP: rs1060503442; hg19: chr12-2791774; COSMIC: COSV59709757; COSMIC: COSV59709757;