NM_006668.2:c.1381C>T

Variant names:

• chr14-99726605-C-T
• rs148881618
• NM_006668.2:c.1381C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_006668.2(CYP46A1):​c.1381C>T​(p.Arg461Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000524 in 1,585,044 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 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: CYP46A1 NM_006668.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.53
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30464983).

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.1381C>T	p.Arg461Trp	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.1381C>T	p.Arg461Trp	missense	Exon 15 of 15	ENSP00000261835.3	Q9Y6A2-1
	CYP46A1	ENST00000900096.1		c.1630C>T	p.Arg544Trp	missense	Exon 16 of 16	ENSP00000570155.1
	CYP46A1	ENST00000900093.1		c.1351C>T	p.Arg451Trp	missense	Exon 15 of 15	ENSP00000570152.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000909 AC: 18 AN: 198020 AF XY: 0.0000842

Gnomad AFR exome AF: 0.0000832

Gnomad AMR exome AF: 0.000243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000818

Gnomad OTH exome AF: 0.000196

GnomAD4 exome AF: 0.0000537 AC: 77 AN: 1432856 Hom.: 0 Cov.: 31 AF XY: 0.0000577 AC XY: 41 AN XY: 710220

African (AFR) AF: 0.0000303 AC: 1 AN: 33046

American (AMR) AF: 0.000249 AC: 10 AN: 40212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25522

East Asian (EAS) AF: 0.00 AC: 0 AN: 38496

South Asian (SAS) AF: 0.0000857 AC: 7 AN: 81668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4416

European-Non Finnish (NFE) AF: 0.0000491 AC: 54 AN: 1099698

Other (OTH) AF: 0.0000844 AC: 5 AN: 59260

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.000131 AC: 2 AN: 15286

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000967 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000502 AC: 6

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	0.26
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.5
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.010	D
Polyphen		0.98	D
Vest4		0.21
MVP		0.65
MPC		1.5
ClinPred		0.18	T
GERP RS		3.9
Varity_R		0.39
gMVP		0.60
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148881618; hg19: chr14-100192942; COSMIC: COSV55893375; COSMIC: COSV55893375;