rs185788586

Positions:

• chr12-2685827-C-A
• chr12-2685827-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000719.7(CACNA1C):​c.5665C>A​(p.Arg1889Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1889C) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.19222829).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5665C>A	p.Arg1889Ser	missense_variant	44/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5665C>A	p.Arg1889Ser	missense_variant	44/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5665C>A	p.Arg1889Ser	missense_variant	44/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5665C>A	p.Arg1889Ser	missense_variant	44/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6004C>A	p.Arg2002Ser	missense_variant	47/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5878C>A	p.Arg1960Ser	missense_variant	45/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5845C>A	p.Arg1949Ser	missense_variant	44/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5830C>A	p.Arg1944Ser	missense_variant	45/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5809C>A	p.Arg1937Ser	missense_variant	46/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5788C>A	p.Arg1930Ser	missense_variant	44/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5770C>A	p.Arg1924Ser	missense_variant	45/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5770C>A	p.Arg1924Ser	missense_variant	45/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5755C>A	p.Arg1919Ser	missense_variant	44/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5755C>A	p.Arg1919Ser	missense_variant	44/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5755C>A	p.Arg1919Ser	missense_variant	44/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5755C>A	p.Arg1919Ser	missense_variant	44/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5749C>A	p.Arg1917Ser	missense_variant	45/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5740C>A	p.Arg1914Ser	missense_variant	45/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5725C>A	p.Arg1909Ser	missense_variant	45/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5722C>A	p.Arg1908Ser	missense_variant	44/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5722C>A	p.Arg1908Ser	missense_variant	44/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5722C>A	p.Arg1908Ser	missense_variant	44/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5716C>A	p.Arg1906Ser	missense_variant	44/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5707C>A	p.Arg1903Ser	missense_variant	44/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5689C>A	p.Arg1897Ser	missense_variant	43/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5689C>A	p.Arg1897Ser	missense_variant	43/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5683C>A	p.Arg1895Ser	missense_variant	43/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5665C>A	p.Arg1889Ser	missense_variant	44/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5665C>A	p.Arg1889Ser	missense_variant	44/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5665C>A	p.Arg1889Ser	missense_variant	44/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5665C>A	p.Arg1889Ser	missense_variant	44/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5665C>A	p.Arg1889Ser	missense_variant	44/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5656C>A	p.Arg1886Ser	missense_variant	44/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5632C>A	p.Arg1878Ser	missense_variant	43/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 23, 2022

The p.R1889S variant (also known as c.5665C>A), located in coding exon 44 of the CACNA1C gene, results from a C to A substitution at nucleotide position 5665. The arginine at codon 1889 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0045	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.19	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	-0.94	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.72	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.18
Sift	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.47	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.15, 0.0040, 0.0060, 0.0030, 0.18, 0.22, 0.0020, 0.071, 0.33, 0.0070, 0.56, 0.065	.;B;B;B;B;B;B;B;B;B;B;B;B;P;B;.;B;B;.;.;.;B;.
Vest4		0.35
MVP		0.48
MPC		0.22
ClinPred		0.62	D
GERP RS		4.3
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: rs185788586; hg19: chr12-2794993;