rs531598856

Positions:

• chr12-2115265-A-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.91A>G​(p.Asn31Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000314 in 1,592,054 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: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.56

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=0.2896582).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.91A>G	p.Asn31Asp	missense_variant	2/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.91A>G	p.Asn31Asp	missense_variant	2/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.91A>G	p.Asn31Asp	missense_variant	2/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.91A>G	p.Asn31Asp	missense_variant	2/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.181A>G	p.Asn61Asp	missense_variant	2/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.91A>G	p.Asn31Asp	missense_variant	2/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.91A>G	p.Asn31Asp	missense_variant	2/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.181A>G	p.Asn61Asp	missense_variant	2/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.91A>G	p.Asn31Asp	missense_variant	2/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.91A>G	p.Asn31Asp	missense_variant	2/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.91A>G	p.Asn31Asp	missense_variant	2/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.91A>G	p.Asn31Asp	missense_variant	2/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.181A>G	p.Asn61Asp	missense_variant	2/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.181A>G	p.Asn61Asp	missense_variant	2/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.181A>G	p.Asn61Asp	missense_variant	2/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.181A>G	p.Asn61Asp	missense_variant	2/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.91A>G	p.Asn31Asp	missense_variant	2/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.91A>G	p.Asn31Asp	missense_variant	2/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.91A>G	p.Asn31Asp	missense_variant	2/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.91A>G	p.Asn31Asp	missense_variant	2/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.91A>G	p.Asn31Asp	missense_variant	2/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.91A>G	p.Asn31Asp	missense_variant	2/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.91A>G	p.Asn31Asp	missense_variant	2/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.91A>G	p.Asn31Asp	missense_variant	2/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.91A>G	p.Asn31Asp	missense_variant	2/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.91A>G	p.Asn31Asp	missense_variant	2/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.91A>G	p.Asn31Asp	missense_variant	2/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.91A>G	p.Asn31Asp	missense_variant	2/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.91A>G	p.Asn31Asp	missense_variant	2/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.91A>G	p.Asn31Asp	missense_variant	2/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.91A>G	p.Asn31Asp	missense_variant	2/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.91A>G	p.Asn31Asp	missense_variant	2/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.91A>G	p.Asn31Asp	missense_variant	2/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.91A>G	p.Asn31Asp	missense_variant	2/46			ENSP00000507309.1
CACNA1C	ENST00000682152.1	c.40A>G	p.Asn14Asp	missense_variant	1/6			ENSP00000506759.1
CACNA1C	ENST00000480911.6	n.91A>G		non_coding_transcript_exon_variant	2/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152258 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000916 AC: 2 AN: 218382 Hom.: 0 AF XY: 0.00000843 AC XY: 1 AN XY: 118678

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000732

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000278 AC: 4 AN: 1439678 Hom.: 0 Cov.: 32 AF XY: 0.00000280 AC XY: 2 AN XY: 713390

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: 0.0000479

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152376 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74526

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 24, 2013

p.Asn31Asp (AAT>GAT): c.91 A>G in exon 2 of the CACNA1C gene (NM_000719.6). The Asn31Asp variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asn31Asp was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Asn31Asp variant results in a semi-conservative amino acid substitution of a neutral Asparagine with a negatively-charged Aspartic acid at a position that is conserved across species. However, in silico analysis predicts Asn31Asp is benign to the protein structure/function. Mutations in nearby residues have not been reported, indicating this region of the protein may tolerate change. With the clinical and molecular information available at this time, we cannot definitively determine if Asn31Asp is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s). -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2020

In summary, this is a rare missense change that is not predicted to affect protein function or cause disease. However, the evidence is insufficient at this time 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 present in population databases (rs531598856, ExAC 0.03%) but has not been reported in the literature in individuals with a CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 190678). This sequence change replaces asparagine with aspartic acid at codon 31 of the CACNA1C protein (p.Asn31Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0090	.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.085	D
MetaRNN	Benign	0.29	T;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	0.88	D
MutationAssessor	Benign	0.0	.;.;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.6	D;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	0.37
Sift	Pathogenic	0.0	D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Pathogenic	0.0	D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.53, 0.075, 0.85, 0.74, 0.42, 0.29	.;.;P;.;B;P;P;P;P;P;B;P;P;B;P;P;P;.;P;P;.;.;.;.
Vest4		0.41, 0.38, 0.39, 0.37, 0.39, 0.40, 0.38, 0.37, 0.38, 0.42, 0.40, 0.37, 0.38, 0.41, 0.40, 0.38, 0.48
MutPred		0.33		.;Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);
MVP		0.91
MPC		2.1
ClinPred		0.53	D
GERP RS		5.8
gMVP		0.55

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: rs531598856; hg19: chr12-2224431;