NM_006668.2:c.1463C>T

Variant names:

• chr14-99726687-C-T
• rs765421364
• NM_006668.2:c.1463C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006668.2(CYP46A1):​c.1463C>T​(p.Pro488Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000181 in 1,548,032 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CYP46A1 NM_006668.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.61
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19142166).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006668.2. 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
	CYP46A1	NM_006668.2	MANE Select	c.1463C>T	p.Pro488Leu	missense	Exon 15 of 15	NP_006659.1	Q9Y6A2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP46A1	ENST00000261835.8	TSL:1 MANE Select	c.1463C>T	p.Pro488Leu	missense	Exon 15 of 15	ENSP00000261835.3	Q9Y6A2-1
	CYP46A1	ENST00000900096.1		c.1712C>T	p.Pro571Leu	missense	Exon 16 of 16	ENSP00000570155.1
	CYP46A1	ENST00000900093.1		c.1433C>T	p.Pro478Leu	missense	Exon 15 of 15	ENSP00000570152.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000338 AC: 5 AN: 148008 AF XY: 0.0000125

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000827

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000546

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000179 AC: 25 AN: 1395914 Hom.: 0 Cov.: 31 AF XY: 0.0000116 AC XY: 8 AN XY: 688270

African (AFR) AF: 0.00 AC: 0 AN: 31760

American (AMR) AF: 0.0000559 AC: 2 AN: 35778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24932

East Asian (EAS) AF: 0.00 AC: 0 AN: 36130

South Asian (SAS) AF: 0.00 AC: 0 AN: 78982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48278

Middle Eastern (MID) AF: 0.000225 AC: 1 AN: 4452

European-Non Finnish (NFE) AF: 0.0000186 AC: 20 AN: 1077944

Other (OTH) AF: 0.0000347 AC: 2 AN: 57658

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152118 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000920 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	-0.070
Eigen_PC	Benign	0.0060
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.84	L
PhyloP100		2.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.011	D
Polyphen		0.92	P
Vest4		0.32
MutPred		0.28		Loss of glycosylation at T485 (P = 0.0443)
MVP		0.43
MPC		1.8
ClinPred		0.25	T
GERP RS		3.9
Varity_R		0.50
gMVP		0.82
Mutation Taster		=59/41	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: rs765421364; hg19: chr14-100193024;