12-2593315-G-C

Variant names:

• chr12-2593315-G-C
• rs1060503446
• NM_000719.7:c.2633G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000719.7(CACNA1C):​c.2633G>C​(p.Ser878Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. S878I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.67
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Timothy syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• long QT syndrome 8

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
• Brugada syndrome 3

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• short QT syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34492218).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.2723G>C	p.Ser908Thr	missense_variant	Exon 19 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.2798G>C	p.Ser933Thr	missense_variant	Exon 20 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.2723G>C	p.Ser908Thr	missense_variant	Exon 19 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.2723G>C	p.Ser908Thr	missense_variant	Exon 19 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.2723G>C	p.Ser908Thr	missense_variant	Exon 19 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.2723G>C	p.Ser908Thr	missense_variant	Exon 19 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2708G>C	p.Ser903Thr	missense_variant	Exon 20 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2708G>C	p.Ser903Thr	missense_variant	Exon 20 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2624G>C	p.Ser875Thr	missense_variant	Exon 19 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2633G>C	p.Ser878Thr	missense_variant	Exon 19 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1240G>C		non_coding_transcript_exon_variant	Exon 17 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1240G>C		3_prime_UTR_variant	Exon 17 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Sep 20, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. 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. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CACNA1C-related disease. This sequence change replaces serine with threonine at codon 878 of the CACNA1C protein (p.Ser878Thr). The serine residue is moderately conserved and there is a small physicochemical difference between serine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CardioboostArm	Benign	0.000055
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.081	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	0.044
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.7	.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
PhyloP100		5.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.38
Sift	Benign	0.099	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	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.0, 0.10, 0.0090, 0.21, 0.0020, 0.99, 0.0050, 0.0080	.;B;B;B;B;B;B;B;B;B;B;B;B;B;D;B;.;B;B;.;B;.;B
Vest4		0.37
MutPred		0.40		.;Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);
MVP		0.89
MPC		1.7
ClinPred		0.95	D
GERP RS		4.9
gMVP		0.74
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs1060503446; hg19: chr12-2702481;