rs199473660

Variant names:

• chr12-2688702-G-A
• rs199473660
• NM_000719.7:c.6040G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2688702-G-A
• chr12-2688702-G-T

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.6040G>A​(p.Val2014Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000249 in 1,610,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. V2014A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:3 O:1
• Conservation: PhyloP100: 4.98
• Publications: 16 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=0.046481907).
• BP6: Variant 12-2688702-G-A is Benign according to our data. Variant chr12-2688702-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67556.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000184 (28/152282) while in subpopulation SAS AF = 0.00124 (6/4830). AF 95% confidence interval is 0.000541. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 28 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.6040G>A	p.Val2014Ile	missense	Exon 46 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.6040G>A	p.Val2014Ile	missense	Exon 46 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.6289G>A	p.Val2097Ile	missense	Exon 49 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.6040G>A	p.Val2014Ile	missense	Exon 46 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.6040G>A	p.Val2014Ile	missense	Exon 46 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.6379G>A	p.Val2127Ile	missense	Exon 49 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000345 AC: 83 AN: 240516 AF XY: 0.000388

Gnomad AFR exome AF: 0.000414

Gnomad AMR exome AF: 0.0000586

Gnomad ASJ exome AF: 0.000511

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000885

Gnomad NFE exome AF: 0.000231

Gnomad OTH exome AF: 0.000339

GnomAD4 exome AF: 0.000256 AC: 373 AN: 1458710 Hom.: 0 Cov.: 33 AF XY: 0.000274 AC XY: 199 AN XY: 725598

African (AFR) AF: 0.0000897 AC: 3 AN: 33436

American (AMR) AF: 0.0000674 AC: 3 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.000768 AC: 20 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.000825 AC: 71 AN: 86066

European-Finnish (FIN) AF: 0.000749 AC: 39 AN: 52070

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

European-Non Finnish (NFE) AF: 0.000203 AC: 225 AN: 1110882

Other (OTH) AF: 0.000199 AC: 12 AN: 60286

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74458

African (AFR) AF: 0.000120 AC: 5 AN: 41556

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000387 Hom.: 0

Bravo AF: 0.000193

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000488 AC: 4

ExAC AF: 0.000357 AC: 43

EpiCase AF: 0.000218

EpiControl AF: 0.000238

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	1	-	Brugada syndrome (shorter-than-normal QT interval) (1)
-	1	-	Brugada syndrome 3 (1)
-	1	-	CACNA1C-related disorder (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	1	-	not specified (1)
-	1	-	Timothy syndrome (1)
-	-	-	Brugada syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
CardioboostArm	Benign	0.00011
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T
Eigen	Benign	0.11
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.85	T
PhyloP100		5.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.12
Sift	Benign	0.051	T
Sift4G	Benign	0.17	T
Polyphen		0.53	P
Vest4		0.49
MVP		0.53
MPC		0.17
ClinPred		0.029	T
GERP RS		5.2
gMVP		0.47
Mutation Taster		=94/6	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: rs199473660; hg19: chr12-2797868; COSMIC: COSV59772541; COSMIC: COSV59772541;