rs28934606

Variant names:

• chr12-57764510-C-G
• rs28934606
• NM_000785.4:c.1004G>C

Your query was ambiguous. Multiple possible variants found:

• chr12-57764510-C-G
• chr12-57764510-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000785.4(CYP27B1):​c.1004G>C​(p.Arg335Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYP27B1 NM_000785.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.46
• Publications: 11 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 12-57764510-C-G is Pathogenic according to our data. Variant chr12-57764510-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 1660.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1004G>C	p.Arg335Pro	missense	Exon 6 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.1004G>C	p.Arg335Pro	missense	Exon 6 of 9	ENSP00000228606.4
	CYP27B1	ENST00000713544.1		c.1085G>C	p.Arg362Pro	missense	Exon 6 of 9	ENSP00000518840.1
	CYP27B1	ENST00000547344.5	TSL:2	n.1143G>C		non_coding_transcript_exon	Exon 5 of 8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Vitamin D-dependent rickets, type 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		2.5
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.93
MutPred		0.81		Gain of catalytic residue at E332 (P = 0.0044)
MVP		0.91
MPC		1.6
ClinPred		1.0	D
GERP RS		2.8
Varity_R		0.99
gMVP		0.91
Mutation Taster		=22/78	disease causing (ClinVar)

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: rs28934606; hg19: chr12-58158293;