chr12-2691032-G-A

Variant names:

• chr12-2691032-G-A
• rs1060503444
• NM_000719.7:c.6250G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4 BS2

The NM_000719.7(CACNA1C):​c.6250G>A​(p.Gly2084Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,450,774 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2084E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.04
• 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]

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32379955).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000719.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.6250G>A	p.Gly2084Arg	missense	Exon 47 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.6250G>A	p.Gly2084Arg	missense	Exon 47 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.6499G>A	p.Gly2167Arg	missense	Exon 50 of 50	NP_955630.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.6250G>A	p.Gly2084Arg	missense	Exon 47 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.6250G>A	p.Gly2084Arg	missense	Exon 47 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.6589G>A	p.Gly2197Arg	missense	Exon 50 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1450774 Hom.: 0 Cov.: 30 AF XY: 0.00000416 AC XY: 3 AN XY: 720722

African (AFR) AF: 0.00 AC: 0 AN: 33218

American (AMR) AF: 0.00 AC: 0 AN: 43120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25878

East Asian (EAS) AF: 0.00 AC: 0 AN: 39030

South Asian (SAS) AF: 0.00 AC: 0 AN: 84412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000452 AC: 5 AN: 1107050

Other (OTH) AF: 0.00 AC: 0 AN: 59952

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	1	-	Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
CardioboostArm	Benign	0.00029
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.014	D
PhyloP100		8.0
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.54
Sift	Benign	0.073	T
Sift4G	Benign	0.16	T
Polyphen		1.0	D
Vest4		0.46
MVP		0.82
MPC		0.83
ClinPred		0.99	D
GERP RS		4.5
gMVP		0.87
Mutation Taster		=62/38	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: rs1060503444; hg19: chr12-2800198; COSMIC: COSV59755889; COSMIC: COSV59755889;