14-99691630-A-G

Position:

• chr14-99691630-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006668.2(CYP46A1):​c.201-150A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 689,676 control chromosomes in the GnomAD database, including 32,595 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 0.27 (6086 hom., cov: 32)
  • Exomes 𝑓: 0.31 (26509 hom.)
• Consequence: CYP46A1 NM_006668.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.591

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP46A1	NM_006668.2	c.201-150A>G		intron_variant		ENST00000261835.8
CYP46A1	XM_011536364.2	c.201-150A>G		intron_variant
CYP46A1	XM_017020933.3	c.44-150A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP46A1	ENST00000261835.8	c.201-150A>G		intron_variant		1	NM_006668.2	P1
	ENST00000555875.1	n.308T>C		non_coding_transcript_exon_variant	3/3	3
CYP46A1	ENST00000554611.5	c.201-150A>G		intron_variant, NMD_transcript_variant		1
CYP46A1	ENST00000380228.6	c.-91-150A>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41181 AN: 151958 Hom.: 6081 Cov.: 32

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.312

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.259

GnomAD4 exome AF: 0.310 AC: 166802 AN: 537600 Hom.: 26509 Cov.: 7 AF XY: 0.311 AC XY: 87735 AN XY: 282328

Gnomad4 AFR exome AF: 0.154

Gnomad4 AMR exome AF: 0.354

Gnomad4 ASJ exome AF: 0.290

Gnomad4 EAS exome AF: 0.380

Gnomad4 SAS exome AF: 0.346

Gnomad4 FIN exome AF: 0.289

Gnomad4 NFE exome AF: 0.307

Gnomad4 OTH exome AF: 0.299

GnomAD4 genome AF: 0.271 AC: 41200 AN: 152076 Hom.: 6086 Cov.: 32 AF XY: 0.271 AC XY: 20168 AN XY: 74324

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.331

Gnomad4 ASJ AF: 0.297

Gnomad4 EAS AF: 0.338

Gnomad4 SAS AF: 0.363

Gnomad4 FIN AF: 0.286

Gnomad4 NFE AF: 0.307

Gnomad4 OTH AF: 0.262

Alfa AF: 0.172 Hom.: 348

Bravo AF: 0.268

Asia WGS AF: 0.354 AC: 1233 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.1
DANN	Benign	0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs754203; hg19: chr14-100157967; COSMIC: COSV55895077;