rs121912775

Variant names:

• chr12-2550020-G-A
• rs121912775
• NM_000719.7:c.1468G>A

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.1468G>A​(p.Gly490Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000399 in 1,605,038 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G490G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (3 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:9 O:2
• Conservation: PhyloP100: 6.48
• Publications: 36 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]

CACNA1C Gene-Disease associations (from GenCC):

• Timothy syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• long QT syndrome

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• long QT syndrome 8

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: ClinGen, Orphanet
• Brugada syndrome 3

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• short QT syndrome

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014768004).
• BP6: Variant 12-2550020-G-A is Benign according to our data. Variant chr12-2550020-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 17634.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000403 (585/1452762) while in subpopulation MID AF = 0.00174 (10/5756). AF 95% confidence interval is 0.000942. There are 3 homozygotes in GnomAdExome4. There are 296 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 56 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.1468G>A	p.Gly490Arg	missense	Exon 10 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.1468G>A	p.Gly490Arg	missense	Exon 10 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.1468G>A	p.Gly490Arg	missense	Exon 10 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.1468G>A	p.Gly490Arg	missense	Exon 10 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.1468G>A	p.Gly490Arg	missense	Exon 10 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.1558G>A	p.Gly520Arg	missense	Exon 10 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000665 AC: 154 AN: 231558 AF XY: 0.000670

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000394

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.0000590

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000239

Gnomad OTH exome AF: 0.000176

GnomAD4 exome AF: 0.000403 AC: 585 AN: 1452762 Hom.: 3 Cov.: 30 AF XY: 0.000410 AC XY: 296 AN XY: 721684

African (AFR) AF: 0.0000600 AC: 2 AN: 33352

American (AMR) AF: 0.000435 AC: 19 AN: 43630

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 329 AN: 25980

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39304

South Asian (SAS) AF: 0.0000949 AC: 8 AN: 84276

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52742

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5756

European-Non Finnish (NFE) AF: 0.000136 AC: 151 AN: 1107658

Other (OTH) AF: 0.00108 AC: 65 AN: 60064

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74438

African (AFR) AF: 0.0000722 AC: 3 AN: 41562

American (AMR) AF: 0.000196 AC: 3 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000569 Hom.: 1

Bravo AF: 0.000442

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000599 AC: 5

ExAC AF: 0.000480 AC: 58

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	not provided (5)
-	-	3	not specified (3)
1	-	-	Brugada syndrome 3 (2)
-	-	1	CACNA1C-related disorder (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Long QT syndrome (1)
-	-	1	Timothy syndrome (1)
-	-	-	Brugada syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
CardioboostArm	Benign	0.000043
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.69
Sift	Benign	0.23	T
Sift4G	Benign	0.29	T
Polyphen		0.99	D
Vest4		0.68
MutPred		0.71		Gain of catalytic residue at N488 (P = 0.0222)
MVP		0.91
MPC		1.4
ClinPred		0.080	T
GERP RS		5.3
gMVP		0.91
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs121912775; hg19: chr12-2659186;