Genetic Variant CYP27A1:n.253C>T (chr2-218782001-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000494263.5(CYP27A1):n.253C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000662 in 604,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000066 ( 0 hom. )

Consequence

CYP27A1
ENST00000494263.5 non_coding_transcript_exon

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.32

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP27A1	NM_000784.4 link	c.-182C>T		upstream_gene_variant		ENST00000258415.9	NP_000775.1	Q02318

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYP27A1	ENST00000494263.5 link	n.253C>T	non_coding_transcript_exon_variant	Exon 1 of 7	2
CYP27A1	ENST00000258415.9 link	c.-182C>T	upstream_gene_variant		1	NM_000784.4	ENSP00000258415.4	Q02318
CYP27A1	ENST00000445971.1 link	n.-182C>T	upstream_gene_variant		5		ENSP00000404945.1	F8WD90
CYP27A1	ENST00000466602.1 link	n.-173C>T	upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000662

AC:

AN:

604662

Hom.:

Cov.:

AF XY:

0.00000651

AC XY:

AN XY:

307034

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

11896

American (AMR)

AF:

0.00

AC:

AN:

12800

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13180

East Asian (EAS)

AF:

0.00

AC:

AN:

26528

South Asian (SAS)

AF:

0.0000238

AC:

AN:

42074

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2218

European-Non Finnish (NFE)

AF:

0.00000458

AC:

AN:

436414

Other (OTH)

AF:

0.0000329

AC:

AN:

30360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cholestanol storage disease

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

5.5

(source)

DANN

Benign

0.72

PhyloP100

-1.3

PromoterAI

0.0095

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over