rs199473391

Variant names:

• chr12-2607117-G-A
• rs199473391
• NM_000719.7:c.3343G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2607117-G-A
• chr12-2607117-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_199460.4(CACNA1C):​c.3403G>A​(p.Glu1135Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1135G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C NM_199460.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:2
• Conservation: PhyloP100: 9.60
• Publications: 26 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-AS3 (HGNC:40117): (CACNA1C antisense RNA 3)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888
• PP5: Variant 12-2607117-G-A is Pathogenic according to our data. Variant chr12-2607117-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 67554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.3343G>A	p.Glu1115Lys	missense	Exon 26 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.3343G>A	p.Glu1115Lys	missense	Exon 26 of 47	NP_001161095.1
	CACNA1C	NM_199460.4		c.3403G>A	p.Glu1135Lys	missense	Exon 27 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.3343G>A	p.Glu1115Lys	missense	Exon 26 of 47	ENSP00000382512.1
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.3343G>A	p.Glu1115Lys	missense	Exon 26 of 47	ENSP00000382563.1
	CACNA1C	ENST00000682544.1		c.3493G>A	p.Glu1165Lys	missense	Exon 27 of 50	ENSP00000507184.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Long QT syndrome 8 (2)
1	-	-	Long QT syndrome (1)
1	-	-	not provided (1)
1	-	-	Timothy syndrome (2)
-	-	-	Brugada syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.76		Gain of catalytic residue at S1132 (P = 0)
MVP		0.98
MPC		2.3
ClinPred		0.99	D
GERP RS		4.9
gMVP		1.0
Mutation Taster		=0/100	disease causing

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: rs199473391; hg19: chr12-2716283; COSMIC: COSV59750786; COSMIC: COSV59750786;