chr12-2053575-A-C

Position:

• chr12-2053575-A-C

Variant summary

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

The NM_000719.7(CACNA1C):​c.13A>C​(p.Asn5His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,448,650 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.89

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 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). 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=0.27259904).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.13A>C	p.Asn5His	missense_variant	1/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.13A>C	p.Asn5His	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.13A>C	p.Asn5His	missense_variant	1/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.13A>C	p.Asn5His	missense_variant	1/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000406454.8	c.13A>C	p.Asn5His	missense_variant	1/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.13A>C	p.Asn5His	missense_variant	1/47	5		ENSP00000382542.2
CACNA1C	ENST00000347598.9	c.13A>C	p.Asn5His	missense_variant	1/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.13A>C	p.Asn5His	missense_variant	1/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.13A>C	p.Asn5His	missense_variant	1/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.13A>C	p.Asn5His	missense_variant	1/48	5		ENSP00000382526.1
CACNA1C	ENST00000399638.5	c.13A>C	p.Asn5His	missense_variant	1/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.13A>C	p.Asn5His	missense_variant	1/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.13A>C	p.Asn5His	missense_variant	1/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.13A>C	p.Asn5His	missense_variant	1/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.13A>C	p.Asn5His	missense_variant	1/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.13A>C	p.Asn5His	missense_variant	1/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.13A>C	p.Asn5His	missense_variant	1/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.13A>C	p.Asn5His	missense_variant	1/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.13A>C	p.Asn5His	missense_variant	1/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.13A>C	p.Asn5His	missense_variant	1/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.13A>C	p.Asn5His	missense_variant	1/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.13A>C	p.Asn5His	missense_variant	1/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.13A>C	p.Asn5His	missense_variant	1/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.13A>C	p.Asn5His	missense_variant	1/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.13A>C	p.Asn5His	missense_variant	1/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.13A>C	p.Asn5His	missense_variant	1/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.13A>C	p.Asn5His	missense_variant	1/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.13A>C	p.Asn5His	missense_variant	1/46			ENSP00000507309.1
CACNA1C	ENST00000682544.1	c.140-61649A>C		intron_variant				ENSP00000507184.1
CACNA1C	ENST00000683824.1	c.140-61649A>C		intron_variant				ENSP00000507867.1
CACNA1C	ENST00000682462.1	c.140-61649A>C		intron_variant				ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.140-61649A>C		intron_variant				ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.140-61649A>C		intron_variant				ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.140-61649A>C		intron_variant				ENSP00000506882.1
CACNA1C	ENST00000480911.6	n.13A>C		non_coding_transcript_exon_variant	1/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1448650 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 719244

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: 0.00000362

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 02, 2021

- -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 18, 2023

This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 5 of the CACNA1C protein (p.Asn5His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 1439077). 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2023

The p.N5H variant (also known as c.13A>C), located in coding exon 1 of the CACNA1C gene, results from an A to C substitution at nucleotide position 13. The asparagine at codon 5 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0086	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.74	D
M_CAP	Pathogenic	0.59	D
MetaRNN	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
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	0.0	.;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	0.88	D
PROVEAN	Benign	-0.40	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	0.33
Sift	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.038	D;D;T;D;D;T;D;D;D;D;D;T;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99, 0.70, 0.80, 0.98, 0.95	.;D;.;P;D;P;D;D;D;D;D;D;P;D;D;D;.;D;D;.;.;.;.
Vest4		0.21
MutPred		0.14		Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);Gain of catalytic residue at T6 (P = 0.0376);
MVP		0.81
MPC		2.3
ClinPred		0.72	D
GERP RS		3.0
gMVP		0.78

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: rs886049150; hg19: chr12-2162741;