12-57765390-C-G

Position:

chr12-57765390-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000785.4(CYP27B1):c.496G>C(p.Val166Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00582 in 1,613,390 control chromosomes in the GnomAD database, including 280 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 17 hom., cov: 33)

Exomes 𝑓: 0.0060 ( 263 hom. )

Consequence

CYP27B1
NM_000785.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.59

Variant links:

Genes affected

CYP27B1 (HGNC:2606): (cytochrome P450 family 27 subfamily B 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. The protein encoded by this gene localizes to the inner mitochondrial membrane where it hydroxylates 25-hydroxyvitamin D3 at the 1alpha position. This reaction synthesizes 1alpha,25-dihydroxyvitamin D3, the active form of vitamin D3, which binds to the vitamin D receptor and regulates calcium metabolism. Thus this enzyme regulates the level of biologically active vitamin D and plays an important role in calcium homeostasis. Mutations in this gene can result in vitamin D-dependent rickets type I. [provided by RefSeq, Jul 2008]

CYP27B1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002989173).

BP6

Variant 12-57765390-C-G is Benign according to our data. Variant chr12-57765390-C-G is described in ClinVar as [Benign]. Clinvar id is 882265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP27B1	NM_000785.4 linkuse as main transcript	c.496G>C	p.Val166Leu	missense_variant	3/9	ENST00000228606.9	NP_000776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP27B1	ENST00000228606.9 linkuse as main transcript	c.496G>C	p.Val166Leu	missense_variant	3/9	1	NM_000785.4	ENSP00000228606	P1

Frequencies

GnomAD3 genomes

AF:

0.00378

AC:

576

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00235

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00404

Gnomad SAS

AF:

0.0672

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00195

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00975

AC:

2401

AN:

246256

Hom.:

AF XY:

0.0121

AC XY:

1625

AN XY:

134114

show subpopulations

Gnomad AFR exome

AF:

0.000585

Gnomad AMR exome

AF:

0.00300

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00285

Gnomad SAS exome

AF:

0.0637

Gnomad FIN exome

AF:

0.000517

Gnomad NFE exome

AF:

0.00205

Gnomad OTH exome

AF:

0.00915

GnomAD4 exome

AF:

0.00602

AC:

8797

AN:

1461012

Hom.:

263

Cov.:

AF XY:

0.00768

AC XY:

5579

AN XY:

726824

show subpopulations

Gnomad4 AFR exome

AF:

0.000836

Gnomad4 AMR exome

AF:

0.00318

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00151

Gnomad4 SAS exome

AF:

0.0631

Gnomad4 FIN exome

AF:

0.000508

Gnomad4 NFE exome

AF:

0.00232

Gnomad4 OTH exome

AF:

0.00851

GnomAD4 genome

AF:

0.00389

AC:

592

AN:

152378

Hom.:

Cov.:

AF XY:

0.00468

AC XY:

349

AN XY:

74520

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.00235

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00405

Gnomad4 SAS

AF:

0.0674

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00195

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.00310

Hom.:

Bravo

AF:

0.00207

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00245

AC:

ExAC

AF:

0.0106

AC:

1284

Asia WGS

AF:

0.0640

AC:

222

AN:

3478

EpiCase

AF:

0.00202

EpiControl

AF:

0.00190

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2019	This variant is associated with the following publications: (PMID: 23423976) -

Vitamin D-dependent rickets, type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.69

DEOGEN2

Benign

0.14

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.2

MutationTaster

Benign

0.76

PrimateAI

Uncertain

0.69

PROVEAN

Benign

0.040

REVEL

Benign

0.10

Sift

Benign

0.57

Sift4G

Benign

0.45

Polyphen

0.015

Vest4

0.15

MutPred

0.26

Gain of catalytic residue at R171 (P = 0.1505);

MPC

0.47

ClinPred

0.036

GERP RS

5.1

Varity_R

0.13

gMVP

0.47

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over