rs8176344

Positions:

• chr12-57765390-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.59

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 -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	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	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.: 13 Cov.: 33

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.: 79 AF XY: 0.0121 AC XY: 1625 AN XY: 134114

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.: 33 AF XY: 0.00768 AC XY: 5579 AN XY: 726824

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.: 17 Cov.: 33 AF XY: 0.00468 AC XY: 349 AN XY: 74520

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.: 6

Bravo AF: 0.00207

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00245 AC: 21

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

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	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Benign	0.69
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	0.76	N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.10
Sift	Benign	0.57	T
Sift4G	Benign	0.45	T
Polyphen		0.015	B
Vest4		0.15
MutPred		0.26		Gain of catalytic residue at R171 (P = 0.1505);
MPC		0.47
ClinPred		0.036	T
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

Other links and lift over

dbSNP: rs8176344; hg19: chr12-58159173;