Genetic Variant CYP2U1:p.Pro151Arg (chr4-107932095-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_183075.3(CYP2U1):c.452C>G(p.Pro151Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,446,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P151Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CYP2U1
NM_183075.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.66

Publications

2 publications found

Variant links:

Genes affected

CYP2U1 (HGNC:20582): (cytochrome P450 family 2 subfamily U 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 enzyme is a hydroxylase that metabolizes arachidonic acid, docosahexaenoic acid, and other long chain fatty acids. [provided by RefSeq, Jul 2008]

CYP2U1 links:

CYP2U1-AS1 (HGNC:54817): (CYP2U1 and SGMS2 antisense RNA 1)

CYP2U1-AS1 links:

LOC107986298 (HGNC:):

LOC107986298 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-107932095-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 433182.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.908

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_183075.3. 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
	CYP2U1	NM_183075.3	MANE Select	c.452C>G	p.Pro151Arg	missense	Exon 1 of 5	NP_898898.1	Q7Z449-1
	CYP2U1-AS1	NR_125929.1		n.25G>C		non_coding_transcript_exon	Exon 1 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP2U1	ENST00000332884.11	TSL:1 MANE Select	c.452C>G	p.Pro151Arg	missense	Exon 1 of 5	ENSP00000333212.6	Q7Z449-1
CYP2U1	ENST00000508453.1	TSL:1	c.-374C>G		5_prime_UTR	Exon 1 of 7	ENSP00000423667.1	E9PGH5
CYP2U1	ENST00000513302.1	TSL:1	n.511C>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000461

AC:

AN:

216904

AF XY:

0.00000842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000104

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1446892

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718384

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33114

American (AMR)

AF:

0.00

AC:

AN:

43058

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25846

East Asian (EAS)

AF:

0.00

AC:

AN:

38710

South Asian (SAS)

AF:

0.00

AC:

AN:

83588

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51104

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1105968

Other (OTH)

AF:

0.00

AC:

AN:

59760

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.62

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

3.3

PhyloP100

4.7

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-7.5

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.049

Polyphen

1.0

Vest4

0.83

MutPred

0.61

Gain of solvent accessibility (P = 0.0411)

MVP

0.83

MPC

0.65

ClinPred

0.99

GERP RS

3.6

PromoterAI

0.0020

Neutral

(source)

Varity_R

0.89

gMVP

0.80

Mutation Taster

=33/67

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over