rs397514515

chr4-107945263-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_183075.3(CYP2U1):c.784T>C(p.Cys262Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C262G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CYP2U1 NM_183075.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.52

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

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-107945263-T-C is Pathogenic according to our data. Variant chr4-107945263-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP2U1	NM_183075.3	c.784T>C	p.Cys262Arg	missense_variant	2/5	ENST00000332884.11
LOC107986298	XR_001741784.2	n.204+33457A>G		intron_variant, non_coding_transcript_variant
CYP2U1	XM_005262717.2	c.838T>C	p.Cys280Arg	missense_variant	2/5
CYP2U1	XM_005262720.2	c.491-2113T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP2U1	ENST00000332884.11	c.784T>C	p.Cys262Arg	missense_variant	2/5	1	NM_183075.3	P1
CYP2U1-AS1	ENST00000656249.1	n.80+33457A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 56 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 25, 2021	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CYP2U1 related disorder (PMID: 23176821, PS1). However, the evidence of pathogenicity is insufficient at this time It is not observed in the gnomAD v2.1.1 dataset (PM2). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 07, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Benign	20
Dann	Benign	0.96
DEOGEN2	Benign	0.079	T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.30
Sift	Benign	0.55	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.13	B;.
Vest4		0.57
MutPred		0.50		Loss of stability (P = 0.0666);.;
MVP		0.67
MPC		0.50
ClinPred		0.55	D
GERP RS		4.4
Varity_R		0.66
gMVP		0.83

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

Other links and lift over

dbSNP: rs397514515; hg19: chr4-108866419;