rs199476204

Positions:

chr4-186209215-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_207352.4(CYP4V2):c.1348C>T(p.Gln450Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CYP4V2
NM_207352.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 0.823

Variant links:

Genes affected

CYP4V2 (HGNC:23198): (cytochrome P450 family 4 subfamily V member 2) This gene encodes a member of the cytochrome P450 hemethiolate protein superfamily which are involved in oxidizing various substrates in the metabolic pathway. It is implicated in the metabolism of fatty acid precursors into n-3 polyunsaturated fatty acids. Mutations in this gene result in Bietti crystalline corneoretinal dystrophy. [provided by RefSeq, Jul 2008]

CYP4V2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-186209215-C-T is Pathogenic according to our data. Variant chr4-186209215-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 39256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186209215-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CYP4V2	NM_207352.4 linkuse as main transcript	c.1348C>T	p.Gln450Ter	stop_gained	10/11	ENST00000378802.5
CYP4V2	XM_005262935.5 linkuse as main transcript	c.1345C>T	p.Gln449Ter	stop_gained	10/11
CYP4V2	XM_047450077.1 linkuse as main transcript	c.952C>T	p.Gln318Ter	stop_gained	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4V2	ENST00000378802.5 linkuse as main transcript	c.1348C>T	p.Gln450Ter	stop_gained	10/11	1	NM_207352.4	P1	Q6ZWL3-1
CYP4V2	ENST00000502665.1 linkuse as main transcript	n.583C>T		non_coding_transcript_exon_variant	4/5	1
CYP4V2	ENST00000507209.5 linkuse as main transcript	n.6046C>T		non_coding_transcript_exon_variant	5/6	1
CYP4V2	ENST00000513354.5 linkuse as main transcript	n.438C>T		non_coding_transcript_exon_variant	4/5	1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Bietti crystalline corneoretinal dystrophy

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2005	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Apr 12, 2012	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 20, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 39256). This premature translational stop signal has been observed in individual(s) with Bietti crystalline dystrophy (PMID: 15937078). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln450*) in the CYP4V2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP4V2 are known to be pathogenic (PMID: 15042513, 25118264). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.14

MutationTaster

Benign

1.0

Vest4

0.78

GERP RS

0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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