rs10151332

Variant names:

• chr14-99722950-C-T
• rs10151332
• NM_006668.2:c.1176+884C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006668.2(CYP46A1):​c.1176+884C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 446,872 control chromosomes in the GnomAD database, including 51,233 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.42 (14994 hom., cov: 31)
  • Exomes 𝑓: 0.49 (36239 hom.)
• Consequence: CYP46A1 NM_006668.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.19
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP46A1	NM_006668.2	MANE Select	c.1176+884C>T		intron	N/A	NP_006659.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP46A1	ENST00000261835.8	TSL:1 MANE Select	c.1176+884C>T		intron	N/A	ENSP00000261835.3
	CYP46A1	ENST00000556313.1	TSL:3	c.*5C>T		3_prime_UTR	Exon 6 of 6	ENSP00000451602.1
	CYP46A1	ENST00000380228.6	TSL:2	c.885+884C>T		intron	N/A	ENSP00000369577.3

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63401 AN: 151776 Hom.: 14979 Cov.: 31

Gnomad AFR AF: 0.187

Gnomad AMI AF: 0.526

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.424

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.506

Gnomad OTH AF: 0.421

GnomAD2 exomes AF: 0.479 AC: 60527 AN: 126366 AF XY: 0.477

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.542

Gnomad ASJ exome AF: 0.433

Gnomad EAS exome AF: 0.382

Gnomad FIN exome AF: 0.600

Gnomad NFE exome AF: 0.504

Gnomad OTH exome AF: 0.467

GnomAD4 exome AF: 0.487 AC: 143698 AN: 294978 Hom.: 36239 Cov.: 0 AF XY: 0.485 AC XY: 81155 AN XY: 167300

African (AFR) AF: 0.180 AC: 1535 AN: 8516

American (AMR) AF: 0.542 AC: 14552 AN: 26830

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 4542 AN: 10586

East Asian (EAS) AF: 0.385 AC: 3460 AN: 8992

South Asian (SAS) AF: 0.475 AC: 27919 AN: 58720

European-Finnish (FIN) AF: 0.585 AC: 7134 AN: 12190

Middle Eastern (MID) AF: 0.408 AC: 1124 AN: 2754

European-Non Finnish (NFE) AF: 0.505 AC: 77121 AN: 152636

Other (OTH) AF: 0.459 AC: 6311 AN: 13754

GnomAD4 genome AF: 0.418 AC: 63435 AN: 151894 Hom.: 14994 Cov.: 31 AF XY: 0.424 AC XY: 31479 AN XY: 74232

African (AFR) AF: 0.186 AC: 7727 AN: 41434

American (AMR) AF: 0.509 AC: 7764 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.424 AC: 1471 AN: 3470

East Asian (EAS) AF: 0.382 AC: 1966 AN: 5144

South Asian (SAS) AF: 0.487 AC: 2332 AN: 4790

European-Finnish (FIN) AF: 0.597 AC: 6307 AN: 10560

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.506 AC: 34378 AN: 67930

Other (OTH) AF: 0.421 AC: 885 AN: 2100

Alfa AF: 0.457 Hom.: 8077

Bravo AF: 0.401

Asia WGS AF: 0.447 AC: 1554 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.12
DANN	Benign	0.44
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs10151332; hg19: chr14-100189287; COSMIC: COSV55894718; COSMIC: COSV55894718;