rs199473392

Variant names:

• chr12-2691170-G-A
• rs199473392
• NM_000719.7:c.6388G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2691170-G-A
• chr12-2691170-G-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000719.7(CACNA1C):​c.6388G>A​(p.Asp2130Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000588 in 1,598,160 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D2130D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3 O:1
• Conservation: PhyloP100: 7.75
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08365455).
• BP6: Variant 12-2691170-G-A is Benign according to our data. Variant chr12-2691170-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 67557.
• BS2: High AC in GnomAd4 at 10 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.6388G>A	p.Asp2130Asn	missense	Exon 47 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.6388G>A	p.Asp2130Asn	missense	Exon 47 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.6637G>A	p.Asp2213Asn	missense	Exon 50 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.6388G>A	p.Asp2130Asn	missense	Exon 47 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.6388G>A	p.Asp2130Asn	missense	Exon 47 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.6727G>A	p.Asp2243Asn	missense	Exon 50 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000117 AC: 28 AN: 240278 AF XY: 0.000115

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00235

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000550

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000581 AC: 84 AN: 1445942 Hom.: 0 Cov.: 30 AF XY: 0.0000544 AC XY: 39 AN XY: 716668

African (AFR) AF: 0.00 AC: 0 AN: 33042

American (AMR) AF: 0.00 AC: 0 AN: 43650

Ashkenazi Jewish (ASJ) AF: 0.00215 AC: 55 AN: 25608

East Asian (EAS) AF: 0.00 AC: 0 AN: 39356

South Asian (SAS) AF: 0.00 AC: 0 AN: 85122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53018

Middle Eastern (MID) AF: 0.000210 AC: 1 AN: 4770

European-Non Finnish (NFE) AF: 0.0000191 AC: 21 AN: 1101844

Other (OTH) AF: 0.000118 AC: 7 AN: 59532

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68036

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.0000898 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000911 AC: 11

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	-	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	Benign	0.27
CardioboostArm	Benign	0.0014
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.47
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.65	T
PhyloP100		7.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.56	P
Vest4		0.31
MVP		0.77
MPC		0.47
ClinPred		0.74	D
GERP RS		4.6
gMVP		0.79
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: rs199473392; hg19: chr12-2800336;