dbSNP rs782203092: CYP2R1:p.Pro493Ala (chr11-14878151-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024514.5(CYP2R1):c.1477C>G(p.Pro493Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P493R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CYP2R1
NM_024514.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.42

Variant links:

Genes affected

CYP2R1 (HGNC:20580): (cytochrome P450 family 2 subfamily R member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This enzyme is a microsomal vitamin D hydroxylase that converts vitamin D into the active ligand for the vitamin D receptor. A mutation in this gene has been associated with selective 25-hydroxyvitamin D deficiency. [provided by RefSeq, Jul 2008]

CYP2R1 links:

PDE3B (HGNC:8779): (phosphodiesterase 3B) Enables 3',5'-cyclic-nucleotide phosphodiesterase activity. Involved in negative regulation of angiogenesis; negative regulation of cell adhesion; and negative regulation of lipid catabolic process. Located in membrane. Part of guanyl-nucleotide exchange factor complex. [provided by Alliance of Genome Resources, Apr 2022]

PDE3B links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20810059).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2R1	NM_024514.5 link	c.1477C>G	p.Pro493Ala	missense_variant	Exon 5 of 5	ENST00000334636.10	NP_078790.2	Q6VVX0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYP2R1	ENST00000334636.10 link	c.1477C>G	p.Pro493Ala	missense_variant	Exon 5 of 5	1	NM_024514.5	ENSP00000334592.5	Q6VVX0
CYP2R1	ENST00000532805.1 link	n.*585C>G		non_coding_transcript_exon_variant	Exon 4 of 4	5		ENSP00000465097.1	E9PS56
CYP2R1	ENST00000532805.1 link	n.*585C>G		3_prime_UTR_variant	Exon 4 of 4	5		ENSP00000465097.1	E9PS56

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250756

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135528

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460968

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726800

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.35

T;.

Eigen

Benign

-0.12

Eigen_PC

Benign

0.00021

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.048

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.1

M;.

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Benign

0.27

Sift

Benign

0.032

D;D

Sift4G

Uncertain

0.034

D;D

Polyphen

0.051

B;B

Vest4

0.090

MutPred

0.58

Loss of glycosylation at P493 (P = 0.0525);.;

MVP

0.82

MPC

0.15

ClinPred

0.74

GERP RS

2.9

Varity_R

0.28

gMVP

0.76

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over