rs34745240

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_207352.4(CYP4V2):c.823G>A(p.Glu275Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0294 in 1,613,724 control chromosomes in the GnomAD database, including 861 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 145 hom., cov: 31)

Exomes 𝑓: 0.029 ( 716 hom. )

Consequence

CYP4V2
NM_207352.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.03

Publications

20 publications found

Variant links:

COSMIC-nc: COSV107498305

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: Laboratory for Molecular Medicine, Illumina, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

CYP4V2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023715794).

BP6

Variant 4-186201178-G-A is Benign according to our data. Variant chr4-186201178-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 263298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0619 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP4V2	NM_207352.4 link	c.823G>A	p.Glu275Lys	missense_variant	Exon 7 of 11	ENST00000378802.5	NP_997235.3	Q6ZWL3-1
CYP4V2	XM_005262935.5 link	c.823G>A	p.Glu275Lys	missense_variant	Exon 7 of 11		XP_005262992.1
CYP4V2	XM_047450077.1 link	c.427G>A	p.Glu143Lys	missense_variant	Exon 5 of 9		XP_047306033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP4V2	ENST00000378802.5 link	c.823G>A	p.Glu275Lys	missense_variant	Exon 7 of 11	1	NM_207352.4	ENSP00000368079.4		Q6ZWL3-1
CYP4V2	ENST00000507209.5 link	n.1664G>A		non_coding_transcript_exon_variant	Exon 3 of 6	1

Frequencies

GnomAD3 genomes

AF:

0.0376

AC:

5714

AN:

152156

Hom.:

146

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0641

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0323

Gnomad ASJ

AF:

0.0389

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00643

Gnomad FIN

AF:

0.0200

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0300

Gnomad OTH

AF:

0.0459

GnomAD2 exomes

AF:

0.0262

AC:

6590

AN:

251296

AF XY:

0.0255

show subpopulations

Gnomad AFR exome

AF:

0.0661

Gnomad AMR exome

AF:

0.0211

Gnomad ASJ exome

AF:

0.0389

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0190

Gnomad NFE exome

AF:

0.0310

Gnomad OTH exome

AF:

0.0316

GnomAD4 exome

AF:

0.0285

AC:

41665

AN:

1461450

Hom.:

716

Cov.:

AF XY:

0.0278

AC XY:

20194

AN XY:

727028

show subpopulations

African (AFR)

AF:

0.0662

AC:

2214

AN:

33458

American (AMR)

AF:

0.0225

AC:

1007

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.0414

AC:

1081

AN:

26114

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00854

AC:

736

AN:

86232

European-Finnish (FIN)

AF:

0.0186

AC:

991

AN:

53402

Middle Eastern (MID)

AF:

0.0572

AC:

330

AN:

5766

European-Non Finnish (NFE)

AF:

0.0300

AC:

33398

AN:

1111718

Other (OTH)

AF:

0.0316

AC:

1907

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

Heterozygous variant carriers

2047

4094

6141

8188

10235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1280

2560

3840

5120

6400

<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:

0.0375

AC:

5711

AN:

152274

Hom.:

145

Cov.:

AF XY:

0.0360

AC XY:

2680

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0639

AC:

2655

AN:

41564

American (AMR)

AF:

0.0323

AC:

494

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0389

AC:

135

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00643

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0200

AC:

213

AN:

10624

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0300

AC:

2039

AN:

68008

Other (OTH)

AF:

0.0450

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

282

564

846

1128

1410

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<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:

0.0324

Hom.:

286

Bravo

AF:

0.0400

TwinsUK

AF:

0.0272

AC:

101

ALSPAC

AF:

0.0267

AC:

103

ESP6500AA

AF:

0.0574

AC:

253

ESP6500EA

AF:

0.0288

AC:

248

ExAC

AF:

0.0272

AC:

3302

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.0333

EpiControl

AF:

0.0348

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bietti crystalline corneoretinal dystrophy

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Corneal dystrophy

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.091

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.62

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.4

REVEL

Benign

0.073

Sift

Benign

0.10

Sift4G

Benign

0.33

Polyphen

0.080

Vest4

0.031

MPC

0.081

ClinPred

0.0065

GERP RS

3.8

Varity_R

0.21

gMVP

0.39

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over