4-186196007-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_207352.4(CYP4V2):c.332T>C(p.Ile111Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000683 in 1,611,540 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I111N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000071 ( 0 hom. )

Consequence

CYP4V2
NM_207352.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.33

Publications

24 publications found

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 Gene-Disease associations (from GenCC):

Bietti crystalline corneoretinal dystrophy
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, G2P, ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet

CYP4V2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 7 curated benign missense variants. Gene score misZ: -0.12103 (below the threshold of 3.09). Trascript score misZ: -0.14191 (below the threshold of 3.09). GenCC associations: The gene is linked to Bietti crystalline corneoretinal dystrophy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.941

PP5

Variant 4-186196007-T-C is Pathogenic according to our data. Variant chr4-186196007-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207352.4. 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
	CYP4V2	NM_207352.4	MANE Select	c.332T>C	p.Ile111Thr	missense	Exon 3 of 11	NP_997235.3	Q6ZWL3-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP4V2	ENST00000378802.5	TSL:1 MANE Select	c.332T>C	p.Ile111Thr	missense	Exon 3 of 11	ENSP00000368079.4	Q6ZWL3-1
CYP4V2	ENST00000905173.1		c.332T>C	p.Ile111Thr	missense	Exon 3 of 12	ENSP00000575232.1
CYP4V2	ENST00000905174.1		c.332T>C	p.Ile111Thr	missense	Exon 3 of 11	ENSP00000575233.1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152218

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000478

AC:

AN:

251184

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000706

AC:

103

AN:

1459322

Hom.:

Cov.:

AF XY:

0.0000771

AC XY:

AN XY:

726160

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33430

American (AMR)

AF:

0.0000224

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53316

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000847

AC:

AN:

1109818

Other (OTH)

AF:

0.0000995

AC:

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000666

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Bietti crystalline corneoretinal dystrophy (4)

not provided (1)

Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.94

MetaSVM

Pathogenic

0.85

MutationAssessor

Pathogenic

3.4

PhyloP100

7.3

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

0.99

Vest4

0.89

MVP

0.97

MPC

0.41

ClinPred

0.91

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

gMVP

0.80

Mutation Taster

=9/91

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over