rs8176344

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V166V) has been classified as Likely 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:4

Conservation

PhyloP100: 2.59

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

vitamin D-dependent rickets, type 1A
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
vitamin D-dependent rickets, type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CYP27B1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000785.4. 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
	CYP27B1	NM_000785.4	MANE Select	c.496G>C	p.Val166Leu	missense	Exon 3 of 9	NP_000776.1	O15528

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP27B1	ENST00000228606.9	TSL:1 MANE Select	c.496G>C	p.Val166Leu	missense	Exon 3 of 9	ENSP00000228606.4	O15528
CYP27B1	ENST00000547451.1	TSL:1	n.296G>C		non_coding_transcript_exon	Exon 1 of 3
CYP27B1	ENST00000713544.1		c.577G>C	p.Val193Leu	missense	Exon 3 of 9	ENSP00000518840.1	A0AAA9YHN9

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

GnomAD2 exomes

AF:

0.00975

AC:

2401

AN:

246256

AF XY:

0.0121

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 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

African (AFR)

AF:

0.000836

AC:

AN:

33474

American (AMR)

AF:

0.00318

AC:

142

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26096

East Asian (EAS)

AF:

0.00151

AC:

AN:

39688

South Asian (SAS)

AF:

0.0631

AC:

5433

AN:

86168

European-Finnish (FIN)

AF:

0.000508

AC:

AN:

53166

Middle Eastern (MID)

AF:

0.00225

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00232

AC:

2580

AN:

1111702

Other (OTH)

AF:

0.00851

AC:

513

AN:

60288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

620

1240

1859

2479

3099

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

296

444

592

740

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00389

AC:

592

AN:

152378

Hom.:

Cov.:

AF XY:

0.00468

AC XY:

349

AN XY:

74520

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

41592

American (AMR)

AF:

0.00235

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00405

AC:

AN:

5188

South Asian (SAS)

AF:

0.0674

AC:

326

AN:

4834

European-Finnish (FIN)

AF:

0.000753

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00195

AC:

133

AN:

68032

Other (OTH)

AF:

0.0104

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Vitamin D-dependent rickets, type 1 (1)

Vitamin D-dependent rickets, type 1A (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

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

PhyloP100

2.6

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

PromoterAI

-0.071

Neutral

(source)

Varity_R

0.13

gMVP

0.47

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over