rs8176344

Variant names:

• chr12-57765390-C-G
• rs8176344
• NM_000785.4:c.496G>C

Variant summary

Our verdict is Benign. The variant received -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. 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.59
• Publications: 14 publications found

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

ACMG classification

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

Selected	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

Ensembl Transcripts

Selected	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
	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

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

GnomAD2 exomes AF: 0.00975 AC: 2401 AN: 246256 AF XY: 0.0121

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

African (AFR) AF: 0.000836 AC: 28 AN: 33474

American (AMR) AF: 0.00318 AC: 142 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26096

East Asian (EAS) AF: 0.00151 AC: 60 AN: 39688

South Asian (SAS) AF: 0.0631 AC: 5433 AN: 86168

European-Finnish (FIN) AF: 0.000508 AC: 27 AN: 53166

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5766

European-Non Finnish (NFE) AF: 0.00232 AC: 2580 AN: 1111702

Other (OTH) AF: 0.00851 AC: 513 AN: 60288

GnomAD4 genome AF: 0.00389 AC: 592 AN: 152378 Hom.: 17 Cov.: 33 AF XY: 0.00468 AC XY: 349 AN XY: 74520

African (AFR) AF: 0.00111 AC: 46 AN: 41592

American (AMR) AF: 0.00235 AC: 36 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00405 AC: 21 AN: 5188

South Asian (SAS) AF: 0.0674 AC: 326 AN: 4834

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00195 AC: 133 AN: 68032

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23423976)

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

May 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Vitamin D-dependent rickets, type 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

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
PhyloP100		2.6
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
PromoterAI		-0.071	Neutral
Varity_R		0.13
gMVP		0.47
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8176344; hg19: chr12-58159173; COSMIC: COSV107208985; COSMIC: COSV107208985;