rs753954220

Variant names:

• chr12-2686169-G-A
• rs753954220
• NM_000719.7:c.5684G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_199460.4(CACNA1C):​c.5933G>A​(p.Arg1978Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1978G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: CACNA1C NM_199460.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 9.26
• Publications: 2 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 -5 ACMG points.

• BP6: Variant 12-2686169-G-A is Benign according to our data. Variant chr12-2686169-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 526961.
• BS2: High AC in GnomAdExome4 at 40 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199460.4. 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.5684G>A	p.Arg1895Gln	missense	Exon 45 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5684G>A	p.Arg1895Gln	missense	Exon 45 of 47	NP_001161095.1
	CACNA1C	NM_199460.4		c.5933G>A	p.Arg1978Gln	missense	Exon 48 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.5684G>A	p.Arg1895Gln	missense	Exon 45 of 47	ENSP00000382512.1
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.5684G>A	p.Arg1895Gln	missense	Exon 45 of 47	ENSP00000382563.1
	CACNA1C	ENST00000682544.1		c.6023G>A	p.Arg2008Gln	missense	Exon 48 of 50	ENSP00000507184.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

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

GnomAD2 exomes AF: 0.0000481 AC: 12 AN: 249302 AF XY: 0.0000370

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461462 Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17 AN XY: 727048

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111670

Other (OTH) AF: 0.000116 AC: 7 AN: 60364

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41576

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000414 AC: 5

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	1	-	Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long QT syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
CardioboostArm	Benign	0.0037
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.015	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.47	T
PhyloP100		9.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.28
Sift	Benign	0.034	D
Sift4G	Uncertain	0.043	D
Polyphen		1.0	D
Vest4		0.78
MVP		0.63
MPC		0.24
ClinPred		0.74	D
GERP RS		4.9
gMVP		0.61
Mutation Taster		=72/28	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: rs753954220; hg19: chr12-2795335; COSMIC: COSV59720154; COSMIC: COSV59720154;