rs1555857966

Positions:

• chr12-2595884-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000719.7(CACNA1C):​c.2674C>G​(p.Gln892Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 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: 6.8e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 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). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. GenCC has associacion of the 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=0.28196794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2674C>G	p.Gln892Glu	missense_variant	20/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2674C>G	p.Gln892Glu	missense_variant	20/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2674C>G	p.Gln892Glu	missense_variant	20/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2674C>G	p.Gln892Glu	missense_variant	20/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2764C>G	p.Gln922Glu	missense_variant	20/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2674C>G	p.Gln892Glu	missense_variant	20/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2674C>G	p.Gln892Glu	missense_variant	20/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2839C>G	p.Gln947Glu	missense_variant	21/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2674C>G	p.Gln892Glu	missense_variant	20/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2674C>G	p.Gln892Glu	missense_variant	20/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2674C>G	p.Gln892Glu	missense_variant	20/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2674C>G	p.Gln892Glu	missense_variant	20/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2764C>G	p.Gln922Glu	missense_variant	20/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2764C>G	p.Gln922Glu	missense_variant	20/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2764C>G	p.Gln922Glu	missense_variant	20/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2764C>G	p.Gln922Glu	missense_variant	20/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2674C>G	p.Gln892Glu	missense_variant	20/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2749C>G	p.Gln917Glu	missense_variant	21/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2674C>G	p.Gln892Glu	missense_variant	20/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2674C>G	p.Gln892Glu	missense_variant	20/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2674C>G	p.Gln892Glu	missense_variant	20/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2674C>G	p.Gln892Glu	missense_variant	20/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2674C>G	p.Gln892Glu	missense_variant	20/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2749C>G	p.Gln917Glu	missense_variant	21/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2674C>G	p.Gln892Glu	missense_variant	20/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2674C>G	p.Gln892Glu	missense_variant	20/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2674C>G	p.Gln892Glu	missense_variant	20/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2674C>G	p.Gln892Glu	missense_variant	20/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2674C>G	p.Gln892Glu	missense_variant	20/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2674C>G	p.Gln892Glu	missense_variant	20/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2674C>G	p.Gln892Glu	missense_variant	20/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2674C>G	p.Gln892Glu	missense_variant	20/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2665C>G	p.Gln889Glu	missense_variant	20/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2674C>G	p.Gln892Glu	missense_variant	20/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1281C>G		non_coding_transcript_exon_variant	18/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1281C>G		3_prime_UTR_variant	18/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461282 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726978

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 29, 2017

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CACNA1C-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with glutamic acid at codon 892 of the CACNA1C protein (p.Gln892Glu). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	0.0069	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.64	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.28	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	0.58	D
MutationAssessor	Benign	1.1	.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.28	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.043, 0.0030, 0.0070, 0.089, 0.052, 0.034, 0.071, 0.33, 0.029, 0.081, 0.37	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;B;.;B
Vest4		0.48
MutPred		0.60		.;Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);Gain of catalytic residue at R890 (P = 0.0101);
MVP		0.76
MPC		1.1
ClinPred		0.25	T
GERP RS		4.9
gMVP		0.72

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: rs1555857966; hg19: chr12-2705050;