4-107931648-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The ENST00000508453(CYP2U1):c.-821C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,259,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000098 ( 0 hom. )

Consequence

CYP2U1
ENST00000508453 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.554

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08596799).

BP6

Variant 4-107931648-C-T is Benign according to our data. Variant chr4-107931648-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 966221.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2U1	NM_183075.3 link	c.5C>T	p.Ser2Leu	missense_variant	Exon 1 of 5	ENST00000332884.11	NP_898898.1	Q7Z449-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2U1	ENST00000332884.11 link	c.5C>T	p.Ser2Leu	missense_variant	Exon 1 of 5	1	NM_183075.3	ENSP00000333212.6		Q7Z449-1

Frequencies

GnomAD3 genomes

AF:

0.000257

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.000773

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000976

AC:

108

AN:

1107088

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

527302

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000243

Gnomad4 ASJ exome

AF:

0.000559

Gnomad4 EAS exome

AF:

0.0000765

Gnomad4 SAS exome

AF:

0.0000379

Gnomad4 FIN exome

AF:

0.000819

Gnomad4 NFE exome

AF:

0.0000682

Gnomad4 OTH exome

AF:

0.000202

GnomAD4 genome

AF:

0.000256

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.000776

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000159

ExAC

AF:

0.000148

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 08, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CYP2U1 c.5C>T (p.Ser2Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 150810 control chromosomes (gnomAD v3.1.2). To our knowledge, no occurrence of c.5C>T in individuals affected with Hereditary Spastic Paraplegia 56 and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CYP2U1: PM2, PP2 -

Spastic paraplegia

Benign:1

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CYP2U1-related disorder

Benign:1

Jan 10, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.093

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.41

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.086

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.0

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.72

REVEL

Benign

0.10

Sift

Uncertain

0.027

Sift4G

Uncertain

0.035

Polyphen

0.20

Vest4

0.17

MVP

0.58

MPC

1.4

ClinPred

0.47

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.055

gMVP

0.21

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over