rs1060503451

Variant names:

• chr12-2690975-G-A
• rs1060503451
• NM_000719.7:c.6193G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2690975-G-A
• chr12-2690975-G-T

Variant summary

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

The NM_000719.7(CACNA1C):​c.6193G>A​(p.Asp2065Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,598,766 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: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.97

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-AS1 (HGNC:):

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

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 the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.30314928).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6193G>A	p.Asp2065Asn	missense_variant	Exon 47 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6193G>A	p.Asp2065Asn	missense_variant	Exon 47 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.6193G>A	p.Asp2065Asn	missense_variant	Exon 47 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6193G>A	p.Asp2065Asn	missense_variant	Exon 47 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6532G>A	p.Asp2178Asn	missense_variant	Exon 50 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6406G>A	p.Asp2136Asn	missense_variant	Exon 48 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6373G>A	p.Asp2125Asn	missense_variant	Exon 47 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6358G>A	p.Asp2120Asn	missense_variant	Exon 48 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6337G>A	p.Asp2113Asn	missense_variant	Exon 49 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6316G>A	p.Asp2106Asn	missense_variant	Exon 47 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6298G>A	p.Asp2100Asn	missense_variant	Exon 48 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6298G>A	p.Asp2100Asn	missense_variant	Exon 48 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6283G>A	p.Asp2095Asn	missense_variant	Exon 47 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6283G>A	p.Asp2095Asn	missense_variant	Exon 47 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6283G>A	p.Asp2095Asn	missense_variant	Exon 47 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6283G>A	p.Asp2095Asn	missense_variant	Exon 47 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6277G>A	p.Asp2093Asn	missense_variant	Exon 48 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6268G>A	p.Asp2090Asn	missense_variant	Exon 48 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6253G>A	p.Asp2085Asn	missense_variant	Exon 48 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6250G>A	p.Asp2084Asn	missense_variant	Exon 47 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6250G>A	p.Asp2084Asn	missense_variant	Exon 47 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6250G>A	p.Asp2084Asn	missense_variant	Exon 47 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6244G>A	p.Asp2082Asn	missense_variant	Exon 47 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6235G>A	p.Asp2079Asn	missense_variant	Exon 47 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6217G>A	p.Asp2073Asn	missense_variant	Exon 46 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6217G>A	p.Asp2073Asn	missense_variant	Exon 46 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6211G>A	p.Asp2071Asn	missense_variant	Exon 46 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6193G>A	p.Asp2065Asn	missense_variant	Exon 47 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6193G>A	p.Asp2065Asn	missense_variant	Exon 47 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6193G>A	p.Asp2065Asn	missense_variant	Exon 47 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6193G>A	p.Asp2065Asn	missense_variant	Exon 47 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6193G>A	p.Asp2065Asn	missense_variant	Exon 47 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.6184G>A	p.Asp2062Asn	missense_variant	Exon 47 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.6160G>A	p.Asp2054Asn	missense_variant	Exon 46 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152242 Hom.: 0 Cov.: 33

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1446524 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 718032

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000234

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: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74384

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Nov 22, 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 with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 aspartic acid with asparagine at codon 2065 of the CACNA1C protein (p.Asp2065Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.043	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.30	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	-0.19	T
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Benign	0.084	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.99, 0.97, 1.0, 0.86, 1.0, 1.0, 0.99, 0.99, 1.0, 0.95	.;D;D;D;P;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;P;.
Vest4		0.36
MVP		0.64
MPC		0.67
ClinPred		0.99	D
GERP RS		3.7
gMVP		0.86

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: rs1060503451; hg19: chr12-2800141;