2-218812681-A-C

Variant names:

• chr2-218812681-A-C
• rs72551317
• NM_000784.4:c.776A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_000784.4(CYP27A1):​c.776A>C​(p.Lys259Thr) 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. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K259R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYP27A1 NM_000784.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.15
• Publications: 2 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-218812681-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 65898.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3837861).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP27A1	NM_000784.4	c.776A>C	p.Lys259Thr	missense_variant	Exon 4 of 9	ENST00000258415.9	NP_000775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP27A1	ENST00000258415.9	c.776A>C	p.Lys259Thr	missense_variant	Exon 4 of 9	1	NM_000784.4	ENSP00000258415.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.0052	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.097
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.3	M;.
PhyloP100		2.2
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Benign	0.24
Sift	Benign	0.064	T;D
Sift4G	Benign	0.19	T;T
Polyphen		0.099	B;.
Vest4		0.41
MutPred		0.60		Loss of methylation at K259 (P = 0.0096);.;
MVP		0.81
MPC		0.24
ClinPred		0.77	D
GERP RS		2.2
Varity_R		0.22
gMVP		0.74
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs72551317; hg19: chr2-219677404;