2-218814154-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000784.4(CYP27A1):c.1151C>T(p.Pro384Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0204 in 1,614,226 control chromosomes in the GnomAD database, including 436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P384P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.015 ( 32 hom., cov: 32)

Exomes 𝑓: 0.021 ( 404 hom. )

Consequence

CYP27A1
NM_000784.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:18O:1

Conservation

PhyloP100: 7.76

Publications

28 publications found

Variant links:

Genes affected

CYP27A1 (HGNC:2605): (cytochrome P450 family 27 subfamily A 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. This mitochondrial protein oxidizes cholesterol intermediates as part of the bile synthesis pathway. Since the conversion of cholesterol to bile acids is the major route for removing cholesterol from the body, this protein is important for overall cholesterol homeostasis. Mutations in this gene cause cerebrotendinous xanthomatosis, a rare autosomal recessive lipid storage disease. [provided by RefSeq, Jul 2008]

CYP27A1 Gene-Disease associations (from GenCC):

cerebrotendinous xanthomatosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Genomics England PanelApp, G2P

CYP27A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1

In a region_of_interest Sterol-binding (size 14) in uniprot entity CP27A_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000784.4

BP4

Computational evidence support a benign effect (MetaRNN=0.01014173).

BP6

Variant 2-218814154-C-T is Benign according to our data. Variant chr2-218814154-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 65831.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0153 (2324/152350) while in subpopulation SAS AF = 0.0302 (146/4832). AF 95% confidence interval is 0.0262. There are 32 homozygotes in GnomAd4. There are 1073 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP27A1	NM_000784.4 link	c.1151C>T	p.Pro384Leu	missense_variant	Exon 6 of 9	ENST00000258415.9	NP_000775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CYP27A1	ENST00000258415.9 link	c.1151C>T	p.Pro384Leu	missense_variant	Exon 6 of 9	1	NM_000784.4	ENSP00000258415.4
CYP27A1	ENST00000494263.5 link	n.1585C>T		non_coding_transcript_exon_variant	Exon 6 of 7	2
CYP27A1	ENST00000445971.1 link	n.*612C>T		downstream_gene_variant		5		ENSP00000404945.1
CYP27A1	ENST00000466602.1 link	n.*63C>T		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0153

AC:

2327

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00480

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.0662

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0304

Gnomad FIN

AF:

0.00349

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0218

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.0190

AC:

4772

AN:

251390

AF XY:

0.0213

show subpopulations

Gnomad AFR exome

AF:

0.00388

Gnomad AMR exome

AF:

0.00833

Gnomad ASJ exome

AF:

0.0607

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00397

Gnomad NFE exome

AF:

0.0228

Gnomad OTH exome

AF:

0.0213

GnomAD4 exome

AF:

0.0210

AC:

30661

AN:

1461876

Hom.:

404

Cov.:

AF XY:

0.0219

AC XY:

15917

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00355

AC:

119

AN:

33480

American (AMR)

AF:

0.00903

AC:

404

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0606

AC:

1583

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0321

AC:

2771

AN:

86256

European-Finnish (FIN)

AF:

0.00459

AC:

245

AN:

53416

Middle Eastern (MID)

AF:

0.0296

AC:

171

AN:

5768

European-Non Finnish (NFE)

AF:

0.0215

AC:

23941

AN:

1112000

Other (OTH)

AF:

0.0236

AC:

1425

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

1974

3948

5921

7895

9869

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

874

1748

2622

3496

4370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0153

AC:

2324

AN:

152350

Hom.:

Cov.:

AF XY:

0.0144

AC XY:

1073

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00479

AC:

199

AN:

41586

American (AMR)

AF:

0.0122

AC:

187

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0662

AC:

230

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.0302

AC:

146

AN:

4832

European-Finnish (FIN)

AF:

0.00349

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0218

AC:

1480

AN:

68040

Other (OTH)

AF:

0.0171

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

123

245

368

490

613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0212

Hom.:

159

Bravo

AF:

0.0151

TwinsUK

AF:

0.0264

AC:

ALSPAC

AF:

0.0205

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0259

AC:

223

ExAC

AF:

0.0188

AC:

2279

Asia WGS

AF:

0.00982

AC:

AN:

3478

EpiCase

AF:

0.0250

EpiControl

AF:

0.0260

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:18Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cholestanol storage disease

Pathogenic:1Uncertain:1Benign:5Other:1

Aug 01, 2013

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The heterozygous p.Pro384Leu variant in CYP27A1 has been identified in 4 individuals with cerebrotendinous xanthomatosis in cis with a frameshift mutation upstream of the variant (PMID: 10775536), and has also been identified in >3% of South Asian chromosomes and 37 total homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for cerebrotendinous xanthomatosis.

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpretted as Pathogenic and reported on 05-03-2012 by Lab or GTR ID 504843. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

May 18, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Nov 01, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Benign:7

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 03, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 12, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP(all): 241/13006=1.8%

Oct 27, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CYP27A1: BS1, BS2

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Oct 05, 2020

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.010

MetaSVM

Uncertain

0.10

MutationAssessor

Pathogenic

3.5

PhyloP100

7.8

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-9.0

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Vest4

0.30

ClinPred

0.12

GERP RS

5.8

Varity_R

0.86

gMVP

0.77

Mutation Taster

=74/26

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over