rs779999297

Variant names:

• chr14-99726707-C-A
• rs779999297
• NM_006668.2:c.1483C>A

Your query was ambiguous. Multiple possible variants found:

• chr14-99726707-C-A
• chr14-99726707-C-G
• chr14-99726707-C-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_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. 15/22 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06203842).

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.1483C>A	p.Pro495Thr	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.1483C>A	p.Pro495Thr	missense	Exon 15 of 15	ENSP00000261835.3	Q9Y6A2-1
	CYP46A1	ENST00000900096.1		c.1732C>A	p.Pro578Thr	missense	Exon 16 of 16	ENSP00000570155.1
	CYP46A1	ENST00000900093.1		c.1453C>A	p.Pro485Thr	missense	Exon 15 of 15	ENSP00000570152.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152024 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.000356 AC: 47 AN: 131850 AF XY: 0.000323

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 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.: 0 Cov.: 31 AF XY: 0.000239 AC XY: 163 AN XY: 680680

African (AFR) AF: 0.0000640 AC: 2 AN: 31226

American (AMR) AF: 0.000527 AC: 18 AN: 34182

Ashkenazi Jewish (ASJ) AF: 0.00124 AC: 30 AN: 24266

East Asian (EAS) AF: 0.00 AC: 0 AN: 35672

South Asian (SAS) AF: 0.00 AC: 0 AN: 77206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4368

European-Non Finnish (NFE) AF: 0.000274 AC: 293 AN: 1071218

Other (OTH) AF: 0.000315 AC: 18 AN: 57066

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152024 Hom.: 0 Cov.: 33 AF XY: 0.000283 AC XY: 21 AN XY: 74230

African (AFR) AF: 0.0000483 AC: 2 AN: 41412

American (AMR) AF: 0.000589 AC: 9 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000280 AC: 19 AN: 67958

Other (OTH) AF: 0.000959 AC: 2 AN: 2086

Alfa AF: 0.000157 Hom.: 0

Bravo AF: 0.000325

ExAC AF: 0.0000513 AC: 5

ClinVar

ClinVar submissions as Germline

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	0.086
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N
PhyloP100		1.6
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.13
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.037	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	T
GERP RS		2.8
Varity_R		0.11
gMVP		0.58
Mutation Taster		=85/15	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: rs779999297; hg19: chr14-100193044;