rs4646536

chr12-57764205-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000785.4(CYP27B1):c.1137-29T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 1,594,334 control chromosomes in the GnomAD database, including 102,530 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.32 (8528 hom., cov: 33)
  • Exomes 𝑓: 0.35 (94002 hom.)
• Consequence: CYP27B1 NM_000785.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.183

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.637 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP27B1	NM_000785.4	c.1137-29T>C		intron_variant		ENST00000228606.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP27B1	ENST00000228606.9	c.1137-29T>C		intron_variant		1	NM_000785.4	P1

Frequencies

GnomAD3 genomes AF: 0.324 AC: 49195 AN: 152066 Hom.: 8503 Cov.: 33

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.384

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.655

Gnomad SAS AF: 0.557

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.153

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.276

GnomAD3 exomes AF: 0.378 AC: 95027 AN: 251222 Hom.: 19719 AF XY: 0.385 AC XY: 52324 AN XY: 135768

Gnomad AFR exome AF: 0.271

Gnomad AMR exome AF: 0.359

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.635

Gnomad SAS exome AF: 0.554

Gnomad FIN exome AF: 0.365

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.326

GnomAD4 exome AF: 0.350 AC: 504508 AN: 1442148 Hom.: 94002 Cov.: 29 AF XY: 0.355 AC XY: 255381 AN XY: 718886

Gnomad4 AFR exome AF: 0.258

Gnomad4 AMR exome AF: 0.349

Gnomad4 ASJ exome AF: 0.288

Gnomad4 EAS exome AF: 0.701

Gnomad4 SAS exome AF: 0.544

Gnomad4 FIN exome AF: 0.358

Gnomad4 NFE exome AF: 0.327

Gnomad4 OTH exome AF: 0.344

GnomAD4 genome AF: 0.324 AC: 49269 AN: 152186 Hom.: 8528 Cov.: 33 AF XY: 0.331 AC XY: 24669 AN XY: 74420

Gnomad4 AFR AF: 0.270

Gnomad4 AMR AF: 0.278

Gnomad4 ASJ AF: 0.286

Gnomad4 EAS AF: 0.655

Gnomad4 SAS AF: 0.558

Gnomad4 FIN AF: 0.378

Gnomad4 NFE AF: 0.319

Gnomad4 OTH AF: 0.282

Alfa AF: 0.327 Hom.: 4688

Bravo AF: 0.311

Asia WGS AF: 0.599 AC: 2079 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	4.0
Dann	Benign	0.66

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: rs4646536; hg19: chr12-58157988; COSMIC: COSV56985739; COSMIC: COSV56985739;