2-218809700-C-G

Position:

chr2-218809700-C-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000784.4(CYP27A1):c.379C>G(p.Arg127Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R127W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CYP27A1
NM_000784.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 0.463

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]

CYP27A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-218809700-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

PP5

Variant 2-218809700-C-G is Pathogenic according to our data. Variant chr2-218809700-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1802246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP27A1	NM_000784.4 linkuse as main transcript	c.379C>G	p.Arg127Gly	missense_variant	2/9	ENST00000258415.9	NP_000775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP27A1	ENST00000258415.9 linkuse as main transcript	c.379C>G	p.Arg127Gly	missense_variant	2/9	1	NM_000784.4	ENSP00000258415	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251374

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727236

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cholestanol storage disease

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 26, 2024	Variant summary: CYP27A1 c.379C>G (p.Arg127Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251374 control chromosomes. c.379C>G has been reported in the literature in at least one homozygous individuals affected with Cerebrotendinous Xanthomatosis (e.g. Shaji_2019). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant located at the same codon (c.379C>T, p.Arg127Trp) has been classified as pathogenic, supporting a critical relevance of this residue to CYP27A1 protein function. The following publication has been ascertained in the context of this evaluation (PMID: 31736580). ClinVar contains an entry for this variant (Variation ID: 1802246). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology	Sep 20, 2022	This variant was identified as a part of carrier screening. The c.379C>G variant is not present in publicly available population databases such as 1000 Genomes, EVS, Indian Exome Database or in our in-house exome database. The variant is present in ExAC and gnomAD at a low frequency. This variant has neither been published in literature nor reported to the ClinVar, Human Genome Mutation Database (HGMD) or OMIM databases, in any affected individuals. An alternative variant (c.379C>T, Arg127Trp) in this position has been previously observed in affected individuals, published several times and reported to clinvar (Accession ID: VCV000065865.22) and HGMD (ID: CM994442) as ‘pathogenic’. In-silico pathogenicity prediction programs like SIFT, Polyphen2, MutationTaster2, CADD etc. predicted this variant to be likely deleterious. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;T

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.094

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.90

D;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.18

MutationAssessor

Pathogenic

3.5

H;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-6.6

D;D

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.91

MutPred

0.88

Gain of relative solvent accessibility (P = 0.0166);.;

MVP

0.85

MPC

0.81

ClinPred

0.98

GERP RS

4.8

Varity_R

0.92

gMVP

0.92

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over