rs8176345

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000785.4(CYP27B1):c.942G>A(p.Leu314Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0278 in 1,614,152 control chromosomes in the GnomAD database, including 720 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 49 hom., cov: 33)

Exomes 𝑓: 0.028 ( 671 hom. )

Consequence

CYP27B1
NM_000785.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.00900

Publications

27 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 12-57764775-C-T is Benign according to our data. Variant chr12-57764775-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 880899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.009 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0212 (3223/152272) while in subpopulation NFE AF = 0.0321 (2180/68000). AF 95% confidence interval is 0.0309. There are 49 homozygotes in GnomAd4. There are 1465 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP27B1	NM_000785.4 link	c.942G>A	p.Leu314Leu	synonymous_variant	Exon 5 of 9	ENST00000228606.9	NP_000776.1	O15528

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP27B1	ENST00000228606.9 link	c.942G>A	p.Leu314Leu	synonymous_variant	Exon 5 of 9	1	NM_000785.4	ENSP00000228606.4		O15528

Frequencies

GnomAD3 genomes

AF:

0.0212

AC:

3225

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00550

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.0210

Gnomad ASJ

AF:

0.0749

Gnomad EAS

AF:

0.000964

Gnomad SAS

AF:

0.00746

Gnomad FIN

AF:

0.00725

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0321

Gnomad OTH

AF:

0.0263

GnomAD2 exomes

AF:

0.0231

AC:

5798

AN:

251472

AF XY:

0.0235

show subpopulations

Gnomad AFR exome

AF:

0.00548

Gnomad AMR exome

AF:

0.0150

Gnomad ASJ exome

AF:

0.0650

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00864

Gnomad NFE exome

AF:

0.0348

Gnomad OTH exome

AF:

0.0271

GnomAD4 exome

AF:

0.0285

AC:

41606

AN:

1461880

Hom.:

671

Cov.:

AF XY:

0.0281

AC XY:

20463

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00469

AC:

157

AN:

33480

American (AMR)

AF:

0.0160

AC:

715

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0707

AC:

1847

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00846

AC:

730

AN:

86258

European-Finnish (FIN)

AF:

0.0102

AC:

543

AN:

53416

Middle Eastern (MID)

AF:

0.0321

AC:

185

AN:

5768

European-Non Finnish (NFE)

AF:

0.0322

AC:

35778

AN:

1112002

Other (OTH)

AF:

0.0273

AC:

1649

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

2583

5165

7748

10330

12913

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1300

2600

3900

5200

6500

<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:

0.0212

AC:

3223

AN:

152272

Hom.:

Cov.:

AF XY:

0.0197

AC XY:

1465

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00548

AC:

228

AN:

41568

American (AMR)

AF:

0.0210

AC:

321

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0749

AC:

260

AN:

3470

East Asian (EAS)

AF:

0.000966

AC:

AN:

5174

South Asian (SAS)

AF:

0.00726

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00725

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0321

AC:

2180

AN:

68000

Other (OTH)

AF:

0.0260

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

162

323

485

646

808

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0310

Hom.:

381

Bravo

AF:

0.0225

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0378

EpiControl

AF:

0.0388

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 28, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Vitamin D-dependent rickets, type 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.44

CADD

Benign

9.7

(source)

DANN

Benign

0.91

PhyloP100

-0.0090

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over