rs10151332

chr14-99722950-C-T

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP46A1	NM_006668.2	c.1176+884C>T		intron_variant		ENST00000261835.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP46A1	ENST00000261835.8	c.1176+884C>T		intron_variant		1	NM_006668.2	P1

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

GnomAD3 exomes AF: 0.479 AC: 60527 AN: 126366 Hom.: 15213 AF XY: 0.477 AC XY: 32990 AN XY: 69224

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 SAS exome AF: 0.476

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

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.542

Gnomad4 ASJ exome AF: 0.429

Gnomad4 EAS exome AF: 0.385

Gnomad4 SAS exome AF: 0.475

Gnomad4 FIN exome AF: 0.585

Gnomad4 NFE exome AF: 0.505

Gnomad4 OTH exome AF: 0.459

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

Gnomad4 AFR AF: 0.186

Gnomad4 AMR AF: 0.509

Gnomad4 ASJ AF: 0.424

Gnomad4 EAS AF: 0.382

Gnomad4 SAS AF: 0.487

Gnomad4 FIN AF: 0.597

Gnomad4 NFE AF: 0.506

Gnomad4 OTH AF: 0.421

Alfa AF: 0.462 Hom.: 5486

Bravo AF: 0.401

Asia WGS AF: 0.447 AC: 1554 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
Cadd	Benign	0.12
Dann	Benign	0.44

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

Publications

LitVar

Other links and lift over

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