4-107945263-T-G

Variant names:

• chr4-107945263-T-G
• rs397514515
• NM_183075.3:c.784T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_183075.3(CYP2U1):​c.784T>G​(p.Cys262Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C262R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CYP2U1 NM_183075.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52
• Publications: 0 publications found

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

LOC107986298 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-107945263-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 39503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27743852).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP2U1	NM_183075.3	c.784T>G	p.Cys262Gly	missense_variant	Exon 2 of 5	ENST00000332884.11	NP_898898.1
CYP2U1	XM_005262717.2	c.838T>G	p.Cys280Gly	missense_variant	Exon 2 of 5		XP_005262774.1
CYP2U1	XM_005262720.2	c.491-2113T>G		intron_variant	Intron 1 of 3		XP_005262777.1
LOC107986298	XR_001741784.2	n.204+33457A>C		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP2U1	ENST00000332884.11	c.784T>G	p.Cys262Gly	missense_variant	Exon 2 of 5	1	NM_183075.3	ENSP00000333212.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Uncertain:1

Dec 16, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Cys262 amino acid residue in CYP2U1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23176821, 29034544). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CYP2U1 protein function. This variant has not been reported in the literature in individuals affected with CYP2U1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 262 of the CYP2U1 protein (p.Cys262Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.88
DEOGEN2	Benign	0.078	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.42	N;.
PhyloP100		2.5
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.66	N;N
REVEL	Benign	0.18
Sift	Benign	0.44	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.0010	B;.
Vest4		0.48
MutPred		0.52		Loss of stability (P = 0.0069);.;
MVP		0.57
MPC		0.27
ClinPred		0.68	D
GERP RS		4.4
Varity_R		0.17
gMVP		0.51
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs397514515; hg19: chr4-108866419;