Genetic Variant CYP46A1:c.201-150A>G (chr14-99691630-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.591

Publications

51 publications found

Variant links:

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]

CYP46A1 links:

ENSG00000258672 (HGNC:):

ENSG00000258672 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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.201-150A>G		intron	N/A	NP_006659.1	Q9Y6A2-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CYP46A1	ENST00000261835.8	TSL:1 MANE Select	c.201-150A>G	intron	N/A	ENSP00000261835.3	Q9Y6A2-1
CYP46A1	ENST00000554611.5	TSL:1	n.201-150A>G	intron	N/A	ENSP00000451069.1	G3V366
CYP46A1	ENST00000900096.1		c.201-150A>G	intron	N/A	ENSP00000570155.1

Frequencies

GnomAD3 genomes

AF:

0.271

AC:

41181

AN:

151958

Hom.:

6081

Cov.:

show subpopulations

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.:

AF XY:

0.311

AC XY:

87735

AN XY:

282328

show subpopulations

African (AFR)

AF:

0.154

AC:

2272

AN:

14748

American (AMR)

AF:

0.354

AC:

8587

AN:

24258

Ashkenazi Jewish (ASJ)

AF:

0.290

AC:

4390

AN:

15152

East Asian (EAS)

AF:

0.380

AC:

12314

AN:

32378

South Asian (SAS)

AF:

0.346

AC:

17317

AN:

50030

European-Finnish (FIN)

AF:

0.289

AC:

12573

AN:

43442

Middle Eastern (MID)

AF:

0.271

AC:

813

AN:

2996

European-Non Finnish (NFE)

AF:

0.307

AC:

99861

AN:

325564

Other (OTH)

AF:

0.299

AC:

8675

AN:

29032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

5528

11056

16585

22113

27641

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1128

2256

3384

4512

5640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.271

AC:

41200

AN:

152076

Hom.:

6086

Cov.:

AF XY:

0.271

AC XY:

20168

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.161

AC:

6694

AN:

41512

American (AMR)

AF:

0.331

AC:

5066

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.297

AC:

1031

AN:

3466

East Asian (EAS)

AF:

0.338

AC:

1735

AN:

5138

South Asian (SAS)

AF:

0.363

AC:

1748

AN:

4812

European-Finnish (FIN)

AF:

0.286

AC:

3030

AN:

10576

Middle Eastern (MID)

AF:

0.315

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.307

AC:

20898

AN:

67970

Other (OTH)

AF:

0.262

AC:

553

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1534

3069

4603

6138

7672

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

434

868

1302

1736

2170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.172

Hom.:

361

Bravo

AF:

0.268

Asia WGS

AF:

0.354

AC:

1233

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

1.1

(source)

DANN

Benign

0.59

PhyloP100

-0.59

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over