2-218787272-A-T

Variant names:

• chr2-218787272-A-T
• rs17470271
• NM_000784.4:c.255+4835A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000784.4(CYP27A1):​c.255+4835A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 152,058 control chromosomes in the GnomAD database, including 10,438 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.36 (10438 hom., cov: 32)
• Consequence: CYP27A1 NM_000784.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.921
• Publications: 33 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: Myriad Women’s Health, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.421 is higher than 0.05.

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.255+4835A>T		intron	N/A	NP_000775.1	Q02318

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP27A1	ENST00000258415.9	TSL:1 MANE Select	c.255+4835A>T		intron	N/A	ENSP00000258415.4	Q02318
	CYP27A1	ENST00000901552.1		c.255+4835A>T		intron	N/A	ENSP00000571611.1
	CYP27A1	ENST00000901553.1		c.255+4835A>T		intron	N/A	ENSP00000571612.1

Frequencies

GnomAD3 genomes AF: 0.357 AC: 54226 AN: 151940 Hom.: 10433 Cov.: 32

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.0635

Gnomad SAS AF: 0.290

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.348

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.357 AC: 54253 AN: 152058 Hom.: 10438 Cov.: 32 AF XY: 0.355 AC XY: 26416 AN XY: 74348

African (AFR) AF: 0.252 AC: 10449 AN: 41484

American (AMR) AF: 0.366 AC: 5592 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1332 AN: 3470

East Asian (EAS) AF: 0.0640 AC: 332 AN: 5188

South Asian (SAS) AF: 0.291 AC: 1406 AN: 4826

European-Finnish (FIN) AF: 0.483 AC: 5100 AN: 10554

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.425 AC: 28884 AN: 67954

Other (OTH) AF: 0.349 AC: 737 AN: 2112

Alfa AF: 0.305 Hom.: 1007

Bravo AF: 0.346

Asia WGS AF: 0.199 AC: 694 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.61
DANN	Benign	0.37
PhyloP100		-0.92
Mutation Taster		=100/0	polymorphism (auto)

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: rs17470271; hg19: chr2-219651995;