12-2053576-A-G

Position:

• chr12-2053576-A-G

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.14A>G​(p.Asn5Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.18

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=0.21796432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.14A>G	p.Asn5Ser	missense_variant	1/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.14A>G	p.Asn5Ser	missense_variant	1/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.14A>G	p.Asn5Ser	missense_variant	1/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.14A>G	p.Asn5Ser	missense_variant	1/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000406454.8	c.14A>G	p.Asn5Ser	missense_variant	1/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.14A>G	p.Asn5Ser	missense_variant	1/47	5		ENSP00000382542.2
CACNA1C	ENST00000347598.9	c.14A>G	p.Asn5Ser	missense_variant	1/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.14A>G	p.Asn5Ser	missense_variant	1/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.14A>G	p.Asn5Ser	missense_variant	1/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.14A>G	p.Asn5Ser	missense_variant	1/48	5		ENSP00000382526.1
CACNA1C	ENST00000399638.5	c.14A>G	p.Asn5Ser	missense_variant	1/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.14A>G	p.Asn5Ser	missense_variant	1/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.14A>G	p.Asn5Ser	missense_variant	1/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.14A>G	p.Asn5Ser	missense_variant	1/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.14A>G	p.Asn5Ser	missense_variant	1/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.14A>G	p.Asn5Ser	missense_variant	1/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.14A>G	p.Asn5Ser	missense_variant	1/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.14A>G	p.Asn5Ser	missense_variant	1/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.14A>G	p.Asn5Ser	missense_variant	1/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.14A>G	p.Asn5Ser	missense_variant	1/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.14A>G	p.Asn5Ser	missense_variant	1/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.14A>G	p.Asn5Ser	missense_variant	1/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.14A>G	p.Asn5Ser	missense_variant	1/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.14A>G	p.Asn5Ser	missense_variant	1/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.14A>G	p.Asn5Ser	missense_variant	1/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.14A>G	p.Asn5Ser	missense_variant	1/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.14A>G	p.Asn5Ser	missense_variant	1/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.14A>G	p.Asn5Ser	missense_variant	1/46			ENSP00000507309.1
CACNA1C	ENST00000682544.1	c.140-61648A>G		intron_variant				ENSP00000507184.1
CACNA1C	ENST00000683824.1	c.140-61648A>G		intron_variant				ENSP00000507867.1
CACNA1C	ENST00000682462.1	c.140-61648A>G		intron_variant				ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.140-61648A>G		intron_variant				ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.140-61648A>G		intron_variant				ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.140-61648A>G		intron_variant				ENSP00000506882.1
CACNA1C	ENST00000480911.6	n.14A>G		non_coding_transcript_exon_variant	1/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 05, 2016

Variant summary: The CACNA1C c.14A>G (p.Asn5Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 52688 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available. -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

This variant is not present in population databases (gnomAD no frequency). 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. 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. ClinVar contains an entry for this variant (Variation ID: 496070). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 5 of the CACNA1C protein (p.Asn5Ser). -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2022

The p.N5S variant (also known as c.14A>G), located in coding exon 1 of the CACNA1C gene, results from an A to G substitution at nucleotide position 14. The asparagine at codon 5 is replaced by serine, 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. 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	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Benign	0.89
DEOGEN2	Benign	0.0057	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.053
FATHMM_MKL	Benign	0.67	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.22	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	0.25	D
MutationAssessor	Benign	-0.69	.;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;.;.;.
MutationTaster	Benign	0.99	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.34	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	0.31
Sift	Benign	0.10	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	0.63	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.93, 0.056, 0.091, 0.015, 0.0050	.;P;.;B;P;B;P;B;P;P;P;B;B;P;P;B;.;P;P;.;.;.;.
Vest4		0.12
MutPred		0.15		Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);Gain of catalytic residue at T6 (P = 0.0155);
MVP		0.68
MPC		2.0
ClinPred		0.63	D
GERP RS		3.0
gMVP		0.76

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: rs1555075958; hg19: chr12-2162742;