4-186191887-C-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

The NM_207352.4(CYP4V2):c.64C>G(p.Leu22Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 1,587,696 control chromosomes in the GnomAD database, including 186,194 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L22H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.46 (16288 hom., cov: 34)
  • Exomes 𝑓: 0.48 (169906 hom.)
• Consequence: CYP4V2 NM_207352.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:14
• Conservation: PhyloP100: -0.996

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-186191888-T-A is described in Lovd as [Likely_pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=3.741501E-5).
• BP6: Variant 4-186191887-C-G is Benign according to our data. Variant chr4-186191887-C-G is described in ClinVar as [Benign]. Clinvar id is 39267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186191887-C-G is described in Lovd as [Benign]. Variant chr4-186191887-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP4V2	NM_207352.4	c.64C>G	p.Leu22Val	missense_variant	1/11	ENST00000378802.5
CYP4V2	XM_005262935.5	c.64C>G	p.Leu22Val	missense_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4V2	ENST00000378802.5	c.64C>G	p.Leu22Val	missense_variant	1/11	1	NM_207352.4	P1

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69750 AN: 151928 Hom.: 16272 Cov.: 34

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.456

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.433

Gnomad NFE AF: 0.506

Gnomad OTH AF: 0.460

GnomAD3 exomes AF: 0.444 AC: 89568 AN: 201924 Hom.: 20187 AF XY: 0.447 AC XY: 49534 AN XY: 110900

Gnomad AFR exome AF: 0.424

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.466

Gnomad EAS exome AF: 0.272

Gnomad SAS exome AF: 0.403

Gnomad FIN exome AF: 0.454

Gnomad NFE exome AF: 0.505

Gnomad OTH exome AF: 0.467

GnomAD4 exome AF: 0.484 AC: 694802 AN: 1435650 Hom.: 169906 Cov.: 75 AF XY: 0.482 AC XY: 343795 AN XY: 712832

Gnomad4 AFR exome AF: 0.425

Gnomad4 AMR exome AF: 0.393

Gnomad4 ASJ exome AF: 0.468

Gnomad4 EAS exome AF: 0.284

Gnomad4 SAS exome AF: 0.405

Gnomad4 FIN exome AF: 0.462

Gnomad4 NFE exome AF: 0.504

Gnomad4 OTH exome AF: 0.472

GnomAD4 genome AF: 0.459 AC: 69805 AN: 152046 Hom.: 16288 Cov.: 34 AF XY: 0.453 AC XY: 33718 AN XY: 74360

Gnomad4 AFR AF: 0.427

Gnomad4 AMR AF: 0.423

Gnomad4 ASJ AF: 0.456

Gnomad4 EAS AF: 0.282

Gnomad4 SAS AF: 0.398

Gnomad4 FIN AF: 0.460

Gnomad4 NFE AF: 0.506

Gnomad4 OTH AF: 0.463

Alfa AF: 0.489 Hom.: 5601

Bravo AF: 0.453

TwinsUK AF: 0.489 AC: 1815

ALSPAC AF: 0.503 AC: 1940

ESP6500AA AF: 0.413 AC: 1786

ESP6500EA AF: 0.489 AC: 4174

ExAC AF: 0.421 AC: 49477

Asia WGS AF: 0.354 AC: 1229 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bietti crystalline corneoretinal dystrophy Pathogenic:1 Benign:5

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Apr 12, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Nov 20, 2020	Population allele frequency is 45% (101,504/227,310 alleles; gnomAD v2.0.2). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as Benign. Following criteria met: BA1 -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 25, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Likely benign, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Corneal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.15
Dann	Benign	0.52
DEOGEN2	Benign	0.050	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0042	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.000037	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.90	N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.027
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.014
MPC		0.11
ClinPred		0.0066	T
GERP RS		0.68
Varity_R		0.039
gMVP		0.50

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: rs1055138; hg19: chr4-187113041; COSMIC: COSV66505124; COSMIC: COSV66505124;