rs201090446

Variant names:

• chr12-2691054-A-G
• rs201090446
• NM_000719.7:c.6272A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-2691054-A-G
• chr12-2691054-A-C

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.6272A>G​(p.Asn2091Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00076 in 1,607,328 control chromosomes in the GnomAD database, including 2 homozygotes. 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. N2091K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (2 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:4
• Conservation: PhyloP100: 3.21
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.054399014).
• BP6: Variant 12-2691054-A-G is Benign according to our data. Variant chr12-2691054-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216482.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000749 (114/152250) while in subpopulation NFE AF = 0.000897 (61/67996). AF 95% confidence interval is 0.000716. There are 0 homozygotes in GnomAd4. There are 54 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 114 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.6272A>G	p.Asn2091Ser	missense	Exon 47 of 47	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.6272A>G	p.Asn2091Ser	missense	Exon 47 of 47	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.6521A>G	p.Asn2174Ser	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.6272A>G	p.Asn2091Ser	missense	Exon 47 of 47	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.6272A>G	p.Asn2091Ser	missense	Exon 47 of 47	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.6611A>G	p.Asn2204Ser	missense	Exon 50 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152132 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000897

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000486 AC: 113 AN: 232392 AF XY: 0.000449

Gnomad AFR exome AF: 0.000600

Gnomad AMR exome AF: 0.000211

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000650

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000663

Gnomad OTH exome AF: 0.00105

GnomAD4 exome AF: 0.000761 AC: 1107 AN: 1455078 Hom.: 2 Cov.: 30 AF XY: 0.000769 AC XY: 556 AN XY: 723254

African (AFR) AF: 0.000690 AC: 23 AN: 33338

American (AMR) AF: 0.000228 AC: 10 AN: 43770

Ashkenazi Jewish (ASJ) AF: 0.0000771 AC: 2 AN: 25950

East Asian (EAS) AF: 0.000330 AC: 13 AN: 39408

South Asian (SAS) AF: 0.000530 AC: 45 AN: 84954

European-Finnish (FIN) AF: 0.0000380 AC: 2 AN: 52694

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5752

European-Non Finnish (NFE) AF: 0.000847 AC: 939 AN: 1109142

Other (OTH) AF: 0.00112 AC: 67 AN: 60070

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000725 AC XY: 54 AN XY: 74446

African (AFR) AF: 0.000866 AC: 36 AN: 41566

American (AMR) AF: 0.000523 AC: 8 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000897 AC: 61 AN: 67996

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000812 Hom.: 0

Bravo AF: 0.000672

ESP6500AA AF: 0.000527 AC: 2

ESP6500EA AF: 0.000611 AC: 5

ExAC AF: 0.000539 AC: 65

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
-	1	1	Cardiovascular phenotype (2)
-	-	1	CACNA1C-related disorder (1)
-	1	-	Cardiac arrhythmia (1)
-	-	1	Long QT syndrome (1)
-	1	-	Timothy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
CardioboostArm	Benign	0.0000064
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.67	T
PhyloP100		3.2
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.14
Sift	Uncertain	0.023	D
Sift4G	Benign	0.30	T
Polyphen		0.99	D
Vest4		0.32
MVP		0.59
MPC		0.21
ClinPred		0.033	T
GERP RS		4.5
gMVP		0.57
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: rs201090446; hg19: chr12-2800220;