rs535350857

Variant names:

• chr12-2685762-G-A
• rs535350857
• NM_000719.7:c.5600G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_000719.7(CACNA1C):​c.5600G>A​(p.Arg1867Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,613,718 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.17

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:):

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

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.13743314).
• BP6: Variant 12-2685762-G-A is Benign according to our data. Variant chr12-2685762-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 518667.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5600G>A	p.Arg1867Gln	missense_variant	Exon 44 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5600G>A	p.Arg1867Gln	missense_variant	Exon 44 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5600G>A	p.Arg1867Gln	missense_variant	Exon 44 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5600G>A	p.Arg1867Gln	missense_variant	Exon 44 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5939G>A	p.Arg1980Gln	missense_variant	Exon 47 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5813G>A	p.Arg1938Gln	missense_variant	Exon 45 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5780G>A	p.Arg1927Gln	missense_variant	Exon 44 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5765G>A	p.Arg1922Gln	missense_variant	Exon 45 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5744G>A	p.Arg1915Gln	missense_variant	Exon 46 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5723G>A	p.Arg1908Gln	missense_variant	Exon 44 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5705G>A	p.Arg1902Gln	missense_variant	Exon 45 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5705G>A	p.Arg1902Gln	missense_variant	Exon 45 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5690G>A	p.Arg1897Gln	missense_variant	Exon 44 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5690G>A	p.Arg1897Gln	missense_variant	Exon 44 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5690G>A	p.Arg1897Gln	missense_variant	Exon 44 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5690G>A	p.Arg1897Gln	missense_variant	Exon 44 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5684G>A	p.Arg1895Gln	missense_variant	Exon 45 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5675G>A	p.Arg1892Gln	missense_variant	Exon 45 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5660G>A	p.Arg1887Gln	missense_variant	Exon 45 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5657G>A	p.Arg1886Gln	missense_variant	Exon 44 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5657G>A	p.Arg1886Gln	missense_variant	Exon 44 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5657G>A	p.Arg1886Gln	missense_variant	Exon 44 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5651G>A	p.Arg1884Gln	missense_variant	Exon 44 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5642G>A	p.Arg1881Gln	missense_variant	Exon 44 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5624G>A	p.Arg1875Gln	missense_variant	Exon 43 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5624G>A	p.Arg1875Gln	missense_variant	Exon 43 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5618G>A	p.Arg1873Gln	missense_variant	Exon 43 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5600G>A	p.Arg1867Gln	missense_variant	Exon 44 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5600G>A	p.Arg1867Gln	missense_variant	Exon 44 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5600G>A	p.Arg1867Gln	missense_variant	Exon 44 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5600G>A	p.Arg1867Gln	missense_variant	Exon 44 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5600G>A	p.Arg1867Gln	missense_variant	Exon 44 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5591G>A	p.Arg1864Gln	missense_variant	Exon 44 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5567G>A	p.Arg1856Gln	missense_variant	Exon 43 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152178 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: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 248922 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135052

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461422 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727000

Gnomad4 AFR exome AF: 0.000209

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: 0.00000540

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74458

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Uncertain:1

Feb 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1867 of the CACNA1C protein (p.Arg1867Gln). This variant is present in population databases (rs535350857, gnomAD 0.002%). 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: 518667). 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. -

Cardiovascular phenotype Uncertain:1

Nov 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1867Q variant (also known as c.5600G>A), located in coding exon 44 of the CACNA1C gene, results from a G to A substitution at nucleotide position 5600. The arginine at codon 1867 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this variant is unlikely to be causative of Timothy syndrome or long QT syndrome; however, its contribution to the development of CACNA1C-related neurodevelopmental disorder is uncertain. -

not provided Benign:1

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1C: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.010	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.065	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	Benign	-0.67	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.91	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.15
Sift	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.95, 0.062, 0.93, 0.33, 0.96, 0.97, 0.80, 0.65, 0.98, 0.89, 1.0, 0.88	.;P;B;P;B;D;D;D;P;P;P;D;P;D;D;.;D;D;.;.;.;P;.
Vest4		0.40
MVP		0.63
MPC		0.43
ClinPred		0.54	D
GERP RS		4.3
gMVP		0.37

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: rs535350857; hg19: chr12-2794928;