Variant 14-99726707-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006668.2(CYP46A1):c.1483C>A(p.Pro495Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00026 in 1,534,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

CYP46A1
NM_006668.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.61

Variant links:

Genes affected

CYP46A1 (HGNC:2641): (cytochrome P450 family 46 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 endoplasmic reticulum protein is expressed in the brain, where it converts cholesterol to 24S-hydroxycholesterol. While cholesterol cannot pass the blood-brain barrier, 24S-hydroxycholesterol can be secreted in the brain into the circulation to be returned to the liver for catabolism. [provided by RefSeq, Jul 2008]

CYP46A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06203842).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP46A1	NM_006668.2 linkuse as main transcript	c.1483C>A	p.Pro495Thr	missense_variant	15/15	ENST00000261835.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP46A1	ENST00000261835.8 linkuse as main transcript	c.1483C>A	p.Pro495Thr	missense_variant	15/15	1	NM_006668.2	P1	Q9Y6A2-1
CYP46A1	ENST00000380228.6 linkuse as main transcript	c.1192C>A	p.Pro398Thr	missense_variant	15/15	2			Q9Y6A2-2
CYP46A1	ENST00000554176.5 linkuse as main transcript	n.1660C>A		non_coding_transcript_exon_variant	10/10	2

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000280

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000356

AC:

AN:

131850

Hom.:

AF XY:

0.000323

AC XY:

AN XY:

71308

show subpopulations

Gnomad AFR exome

AF:

0.000156

Gnomad AMR exome

AF:

0.000617

Gnomad ASJ exome

AF:

0.000981

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000540

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000261

AC:

361

AN:

1382654

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

163

AN XY:

680680

show subpopulations

Gnomad4 AFR exome

AF:

0.0000640

Gnomad4 AMR exome

AF:

0.000527

Gnomad4 ASJ exome

AF:

0.00124

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000274

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000250

AC:

AN:

152024

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74230

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000280

Gnomad4 OTH

AF:

0.000959

Alfa

AF:

0.000157

Hom.:

Bravo

AF:

0.000325

ExAC

AF:

0.0000513

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

The c.1483C>A (p.P495T) alteration is located in exon 15 (coding exon 15) of the CYP46A1 gene. This alteration results from a C to A substitution at nucleotide position 1483, causing the proline (P) at amino acid position 495 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.31

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.23

T;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.062

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.20

N;.

MutationTaster

Benign

0.60

N;N;N

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.070

N;.

REVEL

Benign

0.13

Sift

Uncertain

0.016

D;.

Sift4G

Uncertain

0.037

D;D

Polyphen

0.11

B;.

Vest4

0.31

MutPred

0.25

Gain of phosphorylation at P495 (P = 0.0069);.;

MVP

0.46

MPC

0.99

ClinPred

0.026

GERP RS

2.8

Varity_R

0.11

gMVP

0.58

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