2-218812281-C-G

Variant names:

• chr2-218812281-C-G
• rs59443548
• NM_000784.4:c.506C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000784.4(CYP27A1):​c.506C>G​(p.Ala169Gly) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A169E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP27A1 NM_000784.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1782355).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP27A1	NM_000784.4	c.506C>G	p.Ala169Gly	missense_variant	Exon 3 of 9	ENST00000258415.9	NP_000775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP27A1	ENST00000258415.9	c.506C>G	p.Ala169Gly	missense_variant	Exon 3 of 9	1	NM_000784.4	ENSP00000258415.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cholestanol storage disease Uncertain:1

Aug 26, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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. This variant has not been reported in the literature in individuals affected with CYP27A1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with glycine at codon 169 of the CYP27A1 protein (p.Ala169Gly). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.4	M;.
PhyloP100		1.0
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.071
Sift	Benign	0.18	T;T
Sift4G	Benign	0.077	T;T
Polyphen		0.47	P;.
Vest4		0.099
MutPred		0.25		Gain of ubiquitination at K167 (P = 0.0898);.;
MVP		0.73
MPC		0.19
ClinPred		0.27	T
GERP RS		2.0
Varity_R		0.064
gMVP		0.44
Mutation Taster		=94/6	polymorphism

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: rs59443548; hg19: chr2-219677004;