12-2674532-G-C

Variant names:

• chr12-2674532-G-C
• rs757966245
• ENST00000344100.7:c.4841G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001129829.2(CACNA1C):​c.4841G>C​(p.Arg1614Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. 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. R1614C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CACNA1C NM_001129829.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.589
• 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0688003).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001129829.2. 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.4727-9G>C		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.4727-9G>C		intron	N/A	NP_001161095.1	Q13936-37
	CACNA1C	NM_001129829.2		c.4841G>C	p.Arg1614Pro	missense	Exon 39 of 47	NP_001123301.1	Q13936-14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000344100.7	TSL:1	c.4841G>C	p.Arg1614Pro	missense	Exon 39 of 47	ENSP00000341092.3	Q13936-14
	CACNA1C	ENST00000399621.5	TSL:1	c.4775G>C	p.Arg1592Pro	missense	Exon 39 of 47	ENSP00000382530.1	Q13936-24
	CACNA1C	ENST00000399637.5	TSL:1	c.4775G>C	p.Arg1592Pro	missense	Exon 39 of 47	ENSP00000382546.1	Q13936-27

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402646 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 692200

African (AFR) AF: 0.00 AC: 0 AN: 31810

American (AMR) AF: 0.00 AC: 0 AN: 36048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 36106

South Asian (SAS) AF: 0.00 AC: 0 AN: 79392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080768

Other (OTH) AF: 0.0000172 AC: 1 AN: 58176

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	2.1
DANN	Benign	0.80
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.042	N
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.29	T
PhyloP100		-0.59
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.13
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.078
MutPred		0.38		Gain of catalytic residue at R1614 (P = 0.001)
MVP		0.20
ClinPred		0.061	T
GERP RS		-8.6
Mutation Taster		=93/7	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: rs757966245; hg19: chr12-2783698;