rs200231105

Positions:

• chr12-2685755-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BP6

The NM_000719.7(CACNA1C):​c.5593G>A​(p.Glu1865Lys) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000081 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:8
• Conservation: PhyloP100: 7.58

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]

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 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=0.10103333).
• BP6: Variant 12-2685755-G-A is Benign according to our data. Variant chr12-2685755-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191566.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=2}. Variant chr12-2685755-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5593G>A	p.Glu1865Lys	missense_variant	44/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5593G>A	p.Glu1865Lys	missense_variant	44/47	ENST00000399603.6	NP_001161095.1
CACNA1C-AS1	NR_045725.1	n.333+4385C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5593G>A	p.Glu1865Lys	missense_variant	44/47	5	NM_001167623.2	ENSP00000382512
CACNA1C	ENST00000399655.6	c.5593G>A	p.Glu1865Lys	missense_variant	44/47	1	NM_000719.7	ENSP00000382563
CACNA1C-AS1	ENST00000501371.5	n.294+4385C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 271 AN: 133776 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00245

Gnomad EAS AF: 0.00256

Gnomad SAS AF: 0.000672

Gnomad FIN AF: 0.00413

Gnomad MID AF: 0.00385

Gnomad NFE AF: 0.00224

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.000117 AC: 29 AN: 247782 Hom.: 0 AF XY: 0.0000892 AC XY: 12 AN XY: 134560

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000669

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.0000804

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000810 AC: 118 AN: 1456592 Hom.: 1 Cov.: 31 AF XY: 0.0000801 AC XY: 58 AN XY: 724542

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.0000570

Gnomad4 NFE exome AF: 0.0000622

Gnomad4 OTH exome AF: 0.000150

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00202 AC: 271 AN: 133890 Hom.: 0 Cov.: 32 AF XY: 0.00204 AC XY: 134 AN XY: 65650

Gnomad4 AFR AF: 0.00131

Gnomad4 AMR AF: 0.00184

Gnomad4 ASJ AF: 0.00245

Gnomad4 EAS AF: 0.00257

Gnomad4 SAS AF: 0.000673

Gnomad4 FIN AF: 0.00413

Gnomad4 NFE AF: 0.00224

Gnomad4 OTH AF: 0.00333

Alfa AF: 0.00428 Hom.: 0

ExAC AF: 0.000364 AC: 44

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	CACNA1C: BP4 -

CACNA1C-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 27, 2024

The CACNA1C c.5593G>A variant is predicted to result in the amino acid substitution p.Glu1865Lys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.10% of alleles in individuals of European (Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Mar 11, 2015

- -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 29, 2023

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1865 of the CACNA1C protein (p.Glu1865Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of CACNA1C-related conditions (PMID: 32145446). This variant is also known as c.5617G>A (p.E1873K). ClinVar contains an entry for this variant (Variation ID: 191566). 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. -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Dec 24, 2018

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 28, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.072
Eigen_PC	Benign	-0.014
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.22
Sift	Benign	0.063	T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;T;T;T;T;D;T;D;.
Sift4G	Benign	0.72	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.94, 0.062, 0.33, 0.11, 0.95, 0.96, 0.59, 0.43, 0.98, 0.88, 1.0, 0.92, 0.76	.;P;B;B;B;P;D;D;P;P;B;D;P;D;D;.;D;P;.;.;.;P;.
Vest4		0.58
MVP		0.70
MPC		0.24
ClinPred		0.085	T
GERP RS		3.4
gMVP		0.43

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: rs200231105; hg19: chr12-2794921; COSMIC: COSV59697224; COSMIC: COSV59697224;