chr2-218782197-C-T

Variant names:

• chr2-218782197-C-T
• rs1943396825
• NM_000784.4:c.15C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_000784.4(CYP27A1):​c.15C>T​(p.Gly5Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,366 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CYP27A1 NM_000784.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.260
• 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: Myriad Women’s Health, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 2-218782197-C-T is Benign according to our data. Variant chr2-218782197-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1462401.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.26 with no splicing effect.

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.15C>T	p.Gly5Gly	synonymous	Exon 1 of 9	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.15C>T	p.Gly5Gly	synonymous	Exon 1 of 9	ENSP00000258415.4	Q02318
	CYP27A1	ENST00000901552.1		c.15C>T	p.Gly5Gly	synonymous	Exon 1 of 9	ENSP00000571611.1
	CYP27A1	ENST00000901553.1		c.15C>T	p.Gly5Gly	synonymous	Exon 1 of 9	ENSP00000571612.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1385366 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 683630

African (AFR) AF: 0.00 AC: 0 AN: 31366

American (AMR) AF: 0.00 AC: 0 AN: 35628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25102

East Asian (EAS) AF: 0.00 AC: 0 AN: 35676

South Asian (SAS) AF: 0.00 AC: 0 AN: 79118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 9.28e-7 AC: 1 AN: 1077968

Other (OTH) AF: 0.00 AC: 0 AN: 57642

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Cholestanol storage disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	13
DANN	Benign	0.60
PhyloP100		0.26
PromoterAI		-0.041	Neutral
Mutation Taster		=100/0	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: rs1943396825; hg19: chr2-219646920;