11-14878224-C-G

Position:

• chr11-14878224-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024514.5(CYP2R1):​c.1404G>C​(p.Arg468Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CYP2R1 NM_024514.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0960

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34090358).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP2R1	NM_024514.5	c.1404G>C	p.Arg468Ser	missense_variant	5/5	ENST00000334636.10	NP_078790.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP2R1	ENST00000334636.10	c.1404G>C	p.Arg468Ser	missense_variant	5/5	1	NM_024514.5	ENSP00000334592.5
CYP2R1	ENST00000532805.1	n.*512G>C		non_coding_transcript_exon_variant	4/4	5		ENSP00000465097.1
CYP2R1	ENST00000532805.1	n.*512G>C		3_prime_UTR_variant	4/4	5		ENSP00000465097.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461006 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726818

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000673

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Vitamin D hydroxylation-deficient rickets, type 1B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.3	N;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0030	D;T
Sift4G	Benign	0.081	T;T
Polyphen		0.029	B;B
Vest4		0.50
MutPred		0.61		Loss of catalytic residue at R468 (P = 0.0772);.;
MVP		0.63
MPC		0.27
ClinPred		0.89	D
GERP RS		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.80
gMVP		0.81

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

Other links and lift over

dbSNP: rs1848228813; hg19: chr11-14899770;