12-2679502-C-G

Variant names:

• chr12-2679502-C-G
• rs201492706
• NM_000719.7:c.5150C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000719.7(CACNA1C):​c.5150C>G​(p.Ala1717Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000588 in 1,609,272 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. A1717V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00060 (5 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:9
• Conservation: PhyloP100: 3.62
• Publications: 9 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071842372).
• BP6: Variant 12-2679502-C-G is Benign according to our data. Variant chr12-2679502-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93411.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000499 (76/152314) while in subpopulation AMR AF = 0.00098 (15/15302). AF 95% confidence interval is 0.000604. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 76 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.5150C>G	p.Ala1717Gly	missense	Exon 42 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5150C>G	p.Ala1717Gly	missense	Exon 42 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.5294C>G	p.Ala1765Gly	missense	Exon 44 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.5150C>G	p.Ala1717Gly	missense	Exon 42 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.5150C>G	p.Ala1717Gly	missense	Exon 42 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.5384C>G	p.Ala1795Gly	missense	Exon 44 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000846 AC: 206 AN: 243628 AF XY: 0.000921

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00123

Gnomad ASJ exome AF: 0.00629

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000663

Gnomad OTH exome AF: 0.00168

GnomAD4 exome AF: 0.000597 AC: 870 AN: 1456958 Hom.: 5 Cov.: 31 AF XY: 0.000641 AC XY: 464 AN XY: 724114

African (AFR) AF: 0.000390 AC: 13 AN: 33336

American (AMR) AF: 0.00128 AC: 57 AN: 44360

Ashkenazi Jewish (ASJ) AF: 0.00659 AC: 171 AN: 25968

East Asian (EAS) AF: 0.00 AC: 0 AN: 39576

South Asian (SAS) AF: 0.000559 AC: 48 AN: 85926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53066

Middle Eastern (MID) AF: 0.00852 AC: 49 AN: 5752

European-Non Finnish (NFE) AF: 0.000410 AC: 455 AN: 1108784

Other (OTH) AF: 0.00128 AC: 77 AN: 60190

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74478

African (AFR) AF: 0.000120 AC: 5 AN: 41574

American (AMR) AF: 0.000980 AC: 15 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00107 Hom.: 0

Bravo AF: 0.000646

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000595 AC: 72

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	1	1	Long QT syndrome (2)
-	-	2	not specified (2)
-	-	1	Brugada syndrome (1)
-	-	1	CACNA1C-related disorder (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Restrictive cardiomyopathy;C0023976:Long QT syndrome (1)
-	1	-	Timothy syndrome;C2678478:Brugada syndrome 3;C5774213:Neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures;CN260585:Long QT syndrome 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
CardioboostArm	Benign	0.0000011
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.0072	T
MetaSVM	Uncertain	-0.0047	T
MutationAssessor	Benign	-0.20	N
PhyloP100		3.6
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.27
Sift	Benign	0.059	T
Sift4G	Benign	0.43	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.59
MPC		0.19
ClinPred		0.021	T
GERP RS		3.7
gMVP		0.43
Mutation Taster		=100/0	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: rs201492706; hg19: chr12-2788668;