12-57768302-G-T

Position:

• chr12-57768302-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP5 BP4 BA1

The ENST00000546609.2(CYP27B1):​n.107+578C>A variant causes a intron, non coding transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 151,968 control chromosomes in the GnomAD database, including 6,936 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely risk allele (no stars).

• Frequency: Genomes: 𝑓 0.28 (6936 hom., cov: 32)
• Consequence: CYP27B1 ENST00000546609.2 intron, non_coding_transcript
• Clinical Significance: Likely risk allele no assertion criteria provided P:1
• Conservation: PhyloP100: 0.153

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP5: Variant 12-57768302-G-T is Pathogenic according to our data. Variant chr12-57768302-G-T is described in ClinVar as [Likely_risk_allele]. Clinvar id is 2413182.Status of the report is no_assertion_criteria_provided, 0 stars. We mark this variant Likely_pathogenic, oryginal submission is: [Likely_risk_allele].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83). . Strength limited to SUPPORTING due to the PP5.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP27B1	ENST00000546609.2	n.107+578C>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42276 AN: 151850 Hom.: 6932 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.386

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.285

Gnomad EAS AF: 0.650

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.253

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.278 AC: 42290 AN: 151968 Hom.: 6936 Cov.: 32 AF XY: 0.286 AC XY: 21262 AN XY: 74272

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.262

Gnomad4 ASJ AF: 0.285

Gnomad4 EAS AF: 0.650

Gnomad4 SAS AF: 0.489

Gnomad4 FIN AF: 0.378

Gnomad4 NFE AF: 0.317

Gnomad4 OTH AF: 0.251

Alfa AF: 0.292 Hom.: 7373

Bravo AF: 0.262

Asia WGS AF: 0.520 AC: 1806 AN: 3478

ClinVar

Significance: Likely risk allele

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Vitamin D-dependent rickets, type 1A Pathogenic:1

Likely risk allele, no assertion criteria provided

research

Biology Molecular and Stem Cell Facilities Laboratory, National Cardiovascular Center, Harapan Kita Hospital

Feb 27, 2020

CYP27B1 is the coding gene for 1alpha-hydroxylase enzyme. This enzyme is changed calcidiol into calcitriol. One of the functions of calcitriol is anti-inflammatory -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.5
DANN	Benign	0.60

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10877012; hg19: chr12-58162085;