14-99715894-C-T

Variant names:

• chr14-99715894-C-T
• rs764924761
• NM_006668.2:c.778C>T

Variant summary

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

The NM_006668.2(CYP46A1):​c.778C>T​(p.Arg260Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,630 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: CYP46A1 NM_006668.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.778C>T	p.Arg260Cys	missense	Exon 8 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.778C>T	p.Arg260Cys	missense	Exon 8 of 15	ENSP00000261835.3	Q9Y6A2-1
	CYP46A1	ENST00000900096.1		c.778C>T	p.Arg260Cys	missense	Exon 8 of 16	ENSP00000570155.1
	CYP46A1	ENST00000900093.1		c.778C>T	p.Arg260Cys	missense	Exon 8 of 15	ENSP00000570152.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151980 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00000400 AC: 1 AN: 250058 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461650 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727112

African (AFR) AF: 0.000149 AC: 5 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111940

Other (OTH) AF: 0.0000166 AC: 1 AN: 60382

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151980 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74224

African (AFR) AF: 0.0000242 AC: 1 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67994

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

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	0.15
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		1.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.29
MutPred		0.56		Loss of disorder (P = 0.0138)
MVP		0.69
MPC		1.2
ClinPred		0.94	D
GERP RS		4.4
PromoterAI		-0.011	Neutral
Varity_R		0.35
gMVP		0.61
Mutation Taster		=43/57	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs764924761; hg19: chr14-100182231;