12-2679462-G-C

Variant names:

• chr12-2679462-G-C
• rs758268349
• NM_000719.7:c.5110G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000719.7(CACNA1C):​c.5110G>C​(p.Gly1704Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000701 in 1,425,700 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1704S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.13
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.5110G>C	p.Gly1704Arg	missense	Exon 42 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5110G>C	p.Gly1704Arg	missense	Exon 42 of 47	NP_001161095.1
	CACNA1C	NM_199460.4		c.5254G>C	p.Gly1752Arg	missense	Exon 44 of 50	NP_955630.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.5110G>C	p.Gly1704Arg	missense	Exon 42 of 47	ENSP00000382512.1
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.5110G>C	p.Gly1704Arg	missense	Exon 42 of 47	ENSP00000382563.1
	CACNA1C	ENST00000682544.1		c.5344G>C	p.Gly1782Arg	missense	Exon 44 of 50	ENSP00000507184.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1425700 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 704734

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32754

American (AMR) AF: 0.00 AC: 0 AN: 41892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24118

East Asian (EAS) AF: 0.00 AC: 0 AN: 38662

South Asian (SAS) AF: 0.00 AC: 0 AN: 80120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092486

Other (OTH) AF: 0.0000170 AC: 1 AN: 58818

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
CardioboostArm	Benign	0.00054
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.037	D
Polyphen		1.0	D
Vest4		0.56
MutPred		0.57		Gain of catalytic residue at G1752 (P = 0)
MVP		0.90
MPC		0.30
ClinPred		0.98	D
GERP RS		4.4
gMVP		0.68
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs758268349; hg19: chr12-2788628;