rs730880056

Positions:

• chr12-2593261-G-A
• chr12-2593261-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 7P and 4B. PM1 PM5 PP2 PP3_Moderate BS2

The NM_000719.7(CACNA1C):​c.2579G>A​(p.Arg860Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R860G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4
• Conservation: PhyloP100: 8.08

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.

• PM1: In a region_of_interest Interaction with STAC2 (size 47) in uniprot entity CAC1C_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000719.7
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859
• BS2: High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2579G>A	p.Arg860Gln	missense_variant	19/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2579G>A	p.Arg860Gln	missense_variant	19/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2579G>A	p.Arg860Gln	missense_variant	19/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2579G>A	p.Arg860Gln	missense_variant	19/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2669G>A	p.Arg890Gln	missense_variant	19/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2579G>A	p.Arg860Gln	missense_variant	19/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2579G>A	p.Arg860Gln	missense_variant	19/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2744G>A	p.Arg915Gln	missense_variant	20/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2579G>A	p.Arg860Gln	missense_variant	19/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2579G>A	p.Arg860Gln	missense_variant	19/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2579G>A	p.Arg860Gln	missense_variant	19/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2579G>A	p.Arg860Gln	missense_variant	19/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2669G>A	p.Arg890Gln	missense_variant	19/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2669G>A	p.Arg890Gln	missense_variant	19/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2669G>A	p.Arg890Gln	missense_variant	19/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2669G>A	p.Arg890Gln	missense_variant	19/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2579G>A	p.Arg860Gln	missense_variant	19/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2654G>A	p.Arg885Gln	missense_variant	20/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2579G>A	p.Arg860Gln	missense_variant	19/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2579G>A	p.Arg860Gln	missense_variant	19/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2579G>A	p.Arg860Gln	missense_variant	19/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2579G>A	p.Arg860Gln	missense_variant	19/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2579G>A	p.Arg860Gln	missense_variant	19/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2654G>A	p.Arg885Gln	missense_variant	20/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2579G>A	p.Arg860Gln	missense_variant	19/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2579G>A	p.Arg860Gln	missense_variant	19/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2579G>A	p.Arg860Gln	missense_variant	19/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2579G>A	p.Arg860Gln	missense_variant	19/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2579G>A	p.Arg860Gln	missense_variant	19/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2579G>A	p.Arg860Gln	missense_variant	19/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2579G>A	p.Arg860Gln	missense_variant	19/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2579G>A	p.Arg860Gln	missense_variant	19/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2570G>A	p.Arg857Gln	missense_variant	19/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2579G>A	p.Arg860Gln	missense_variant	19/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1186G>A		non_coding_transcript_exon_variant	17/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1186G>A		3_prime_UTR_variant	17/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248588 Hom.: 0 AF XY: 0.0000223 AC XY: 3 AN XY: 134824

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461408 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 726928

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

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

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2021	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28616568, 29071820, 28600387) -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Timothy syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Mar 25, 2019

- -

Wolff-Parkinson-White pattern Uncertain:1

Uncertain significance, no assertion criteria provided

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Jul 14, 2017

This variant was identified in an individual with Wolff-Parkinson-White syndrome -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 15, 2021

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. This variant disrupts the p.Arg860 amino acid residue in CACNA1C. Other variant(s) that disrupt this residue have been observed in individuals with CACNA1C-related conditions (PMID: 25633834; Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 190654). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 28600387, 28616568, 29071820, 31408100; Invitae). This variant is present in population databases (rs730880056, ExAC 0.003%). This sequence change replaces arginine with glutamine at codon 860 of the CACNA1C protein (p.Arg860Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2020

The p.R860Q variant (also known as c.2579G>A), located in coding exon 19 of the CACNA1C gene, results from a G to A substitution at nucleotide position 2579. The arginine at codon 860 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in long QT syndrome (LQTS) cases; however, in some cases clinical details were limited and/or an additional cardiac variant was also detected (Mellor G et al. Circ Cardiovasc Genet, 2017 Jun;10:[Epub ahead of print]; Boles U et al. Int J Cardiol Heart Vasc, 2017 Jun;15:21-23; Seo SH et al. Ann Lab Med, 2018 Jan;38:54-58). Alternate amino acid substitutions at this codon, p.R860G and p.R860P, have also been associated with LQTS (Mellor GJ et al. Europace, 2019 Nov;21:1725-1732). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.062	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.86	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	1.1	D
MutationAssessor	Uncertain	2.2	.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.9	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	0.65
Sift	Benign	0.057	T;T;D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;D
Sift4G	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0, 1.0, 0.77, 0.41, 0.88, 1.0, 1.0	.;D;D;P;B;P;D;D;D;P;D;D;D;D;D;D;.;D;D;.;D;.;D
Vest4		0.79
MVP		0.94
MPC		2.0
ClinPred		0.86	D
GERP RS		4.9
gMVP		0.80

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: rs730880056; hg19: chr12-2702427;