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GeneBe

2-218782211-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000784.4(CYP27A1):c.29G>A(p.Arg10Lys) 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 benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CYP27A1
NM_000784.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.942
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.23350826).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CYP27A1NM_000784.4 linkuse as main transcriptc.29G>A p.Arg10Lys missense_variant 1/9 ENST00000258415.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CYP27A1ENST00000258415.9 linkuse as main transcriptc.29G>A p.Arg10Lys missense_variant 1/91 NM_000784.4 P1
CYP27A1ENST00000466602.1 linkuse as main transcriptn.38G>A non_coding_transcript_exon_variant 1/32
CYP27A1ENST00000494263.5 linkuse as main transcriptn.463G>A non_coding_transcript_exon_variant 1/72
CYP27A1ENST00000445971.1 linkuse as main transcriptc.29G>A p.Arg10Lys missense_variant, NMD_transcript_variant 1/55

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1387332
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
684484
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cholestanol storage disease Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJul 01, 2022This variant has not been reported in the literature in individuals affected with CYP27A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 10 of the CYP27A1 protein (p.Arg10Lys). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CYP27A1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Benign
-0.046
T
BayesDel_noAF
Benign
-0.30
Cadd
Benign
22
Dann
Benign
0.70
DEOGEN2
Benign
0.19
T
Eigen
Benign
-0.65
Eigen_PC
Benign
-0.63
FATHMM_MKL
Benign
0.67
D
LIST_S2
Benign
0.65
T
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.23
T
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
1.0
L
MutationTaster
Benign
1.0
N
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-0.48
N
REVEL
Benign
0.14
Sift
Benign
0.11
T
Sift4G
Benign
0.44
T
Polyphen
0.23
B
Vest4
0.37
MutPred
0.41
Loss of methylation at R10 (P = 0.0221);
MVP
0.63
MPC
0.18
ClinPred
0.076
T
GERP RS
1.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.058
gMVP
0.39

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1943397146; hg19: chr2-219646934; API