rs182208896

Variant names:

• chr12-2685801-G-A
• rs182208896
• NM_000719.7:c.5639G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2685801-G-A
• chr12-2685801-G-C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000719.7(CACNA1C):​c.5639G>A​(p.Arg1880Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000333 in 1,613,700 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (3 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 1.50
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006205976).
• BP6: Variant 12-2685801-G-A is Benign according to our data. Variant chr12-2685801-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 67555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 55 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.5639G>A	p.Arg1880Gln	missense	Exon 44 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5639G>A	p.Arg1880Gln	missense	Exon 44 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.5888G>A	p.Arg1963Gln	missense	Exon 47 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.5639G>A	p.Arg1880Gln	missense	Exon 44 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.5639G>A	p.Arg1880Gln	missense	Exon 44 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.5978G>A	p.Arg1993Gln	missense	Exon 47 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152182 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000651 AC: 162 AN: 248942 AF XY: 0.000637

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.000723

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.000331 AC: 483 AN: 1461400 Hom.: 3 Cov.: 31 AF XY: 0.000344 AC XY: 250 AN XY: 727000

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0119 AC: 310 AN: 26130

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000864 AC: 96 AN: 1111620

Other (OTH) AF: 0.000944 AC: 57 AN: 60352

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152300 Hom.: 1 Cov.: 32 AF XY: 0.000389 AC XY: 29 AN XY: 74462

African (AFR) AF: 0.0000241 AC: 1 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 44 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68022

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

Alfa AF: 0.000929 Hom.: 0

Bravo AF: 0.000336

ESP6500AA AF: 0.000251 AC: 1

ESP6500EA AF: 0.000720 AC: 6

ExAC AF: 0.000488 AC: 59

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
CardioboostArm	Benign	0.000012
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.70	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.5
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.076
Sift	Benign	0.36	T
Sift4G	Benign	0.38	T
Polyphen		0.0010	B
Vest4		0.20
MVP		0.42
MPC		0.22
ClinPred		0.014	T
GERP RS		1.4
gMVP		0.33
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: rs182208896; hg19: chr12-2794967; COSMIC: COSV59737130; COSMIC: COSV59737130;