chr2-218812299-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000784.4(CYP27A1):c.524C>T(p.Thr175Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,614,132 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T175T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0046 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00082 ( 6 hom. )

Consequence

CYP27A1
NM_000784.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.55

Publications

8 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: Myriad Women’s Health, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen

CYP27A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0065559447).

BP6

Variant 2-218812299-C-T is Benign according to our data. Variant chr2-218812299-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 586209.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00463 (705/152302) while in subpopulation AFR AF = 0.0146 (605/41562). AF 95% confidence interval is 0.0136. There are 3 homozygotes in GnomAd4. There are 318 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000784.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP27A1	NM_000784.4	MANE Select	c.524C>T	p.Thr175Met	missense	Exon 3 of 9	NP_000775.1	Q02318

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP27A1	ENST00000258415.9	TSL:1 MANE Select	c.524C>T	p.Thr175Met	missense	Exon 3 of 9	ENSP00000258415.4	Q02318
CYP27A1	ENST00000901552.1		c.524C>T	p.Thr175Met	missense	Exon 3 of 9	ENSP00000571611.1
CYP27A1	ENST00000901553.1		c.524C>T	p.Thr175Met	missense	Exon 3 of 9	ENSP00000571612.1

Frequencies

GnomAD3 genomes

AF:

0.00461

AC:

702

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.00716

GnomAD2 exomes

AF:

0.00145

AC:

365

AN:

251472

AF XY:

0.00115

show subpopulations

Gnomad AFR exome

AF:

0.0158

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000519

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.000817

AC:

1194

AN:

1461830

Hom.:

Cov.:

AF XY:

0.000773

AC XY:

562

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.0143

AC:

478

AN:

33480

American (AMR)

AF:

0.00125

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000481

AC:

535

AN:

1111954

Other (OTH)

AF:

0.00161

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

149

223

298

372

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00463

AC:

705

AN:

152302

Hom.:

Cov.:

AF XY:

0.00427

AC XY:

318

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0146

AC:

605

AN:

41562

American (AMR)

AF:

0.00203

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000750

AC:

AN:

68018

Other (OTH)

AF:

0.00709

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

116

154

193

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00179

Hom.:

Bravo

AF:

0.00491

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0166

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00169

AC:

205

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.000948

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Cholestanol storage disease (2)

Cardiovascular phenotype (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.081

FATHMM_MKL

Benign

0.29

LIST_S2

Uncertain

0.90

MetaRNN

Benign

0.0066

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.8

PhyloP100

1.5

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.25

Sift

Uncertain

0.011

Sift4G

Uncertain

0.033

Polyphen

1.0

Vest4

0.33

MVP

0.85

MPC

0.68

ClinPred

0.028

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.091

gMVP

0.50

Mutation Taster

=92/8

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over