rs13146272

Positions:

• chr4-186199057-C-A
• chr4-186199057-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000378802.5(CYP4V2):​c.775C>A​(p.Gln259Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.617 in 1,612,180 control chromosomes in the GnomAD database, including 310,979 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28214 hom., cov: 32)
  • Exomes 𝑓: 0.62 (282765 hom.)
• Consequence: CYP4V2 ENST00000378802.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.23

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.9090473E-6).
• BP6: Variant 4-186199057-C-A is Benign according to our data. Variant chr4-186199057-C-A is described in ClinVar as [Benign]. Clinvar id is 263297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186199057-C-A is described in Lovd as [Pathogenic]. Variant chr4-186199057-C-A is described in Lovd as [Benign]. Variant chr4-186199057-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.635 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP4V2	NM_207352.4	c.775C>A	p.Gln259Lys	missense_variant	6/11	ENST00000378802.5	NP_997235.3
CYP4V2	XM_005262935.5	c.775C>A	p.Gln259Lys	missense_variant	6/11		XP_005262992.1
CYP4V2	XM_047450077.1	c.379C>A	p.Gln127Lys	missense_variant	4/9		XP_047306033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP4V2	ENST00000378802.5	c.775C>A	p.Gln259Lys	missense_variant	6/11	1	NM_207352.4	ENSP00000368079	P1
CYP4V2	ENST00000507209.5	n.1616C>A		non_coding_transcript_exon_variant	2/6	1

Frequencies

GnomAD3 genomes AF: 0.606 AC: 92014 AN: 151902 Hom.: 28197 Cov.: 32

Gnomad AFR AF: 0.610

Gnomad AMI AF: 0.681

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.416

Gnomad SAS AF: 0.606

Gnomad FIN AF: 0.662

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.640

Gnomad OTH AF: 0.593

GnomAD3 exomes AF: 0.573 AC: 144116 AN: 251344 Hom.: 42896 AF XY: 0.583 AC XY: 79201 AN XY: 135848

Gnomad AFR exome AF: 0.616

Gnomad AMR exome AF: 0.373

Gnomad ASJ exome AF: 0.517

Gnomad EAS exome AF: 0.393

Gnomad SAS exome AF: 0.606

Gnomad FIN exome AF: 0.664

Gnomad NFE exome AF: 0.637

Gnomad OTH exome AF: 0.567

GnomAD4 exome AF: 0.618 AC: 902697 AN: 1460160 Hom.: 282765 Cov.: 49 AF XY: 0.619 AC XY: 449627 AN XY: 726452

Gnomad4 AFR exome AF: 0.603

Gnomad4 AMR exome AF: 0.383

Gnomad4 ASJ exome AF: 0.521

Gnomad4 EAS exome AF: 0.388

Gnomad4 SAS exome AF: 0.604

Gnomad4 FIN exome AF: 0.666

Gnomad4 NFE exome AF: 0.639

Gnomad4 OTH exome AF: 0.601

GnomAD4 genome AF: 0.606 AC: 92073 AN: 152020 Hom.: 28214 Cov.: 32 AF XY: 0.605 AC XY: 44982 AN XY: 74316

Gnomad4 AFR AF: 0.610

Gnomad4 AMR AF: 0.489

Gnomad4 ASJ AF: 0.510

Gnomad4 EAS AF: 0.416

Gnomad4 SAS AF: 0.606

Gnomad4 FIN AF: 0.662

Gnomad4 NFE AF: 0.640

Gnomad4 OTH AF: 0.595

Alfa AF: 0.613 Hom.: 71938

Bravo AF: 0.584

TwinsUK AF: 0.640 AC: 2373

ALSPAC AF: 0.636 AC: 2451

ESP6500AA AF: 0.624 AC: 2749

ESP6500EA AF: 0.630 AC: 5422

ExAC AF: 0.585 AC: 71038

Asia WGS AF: 0.529 AC: 1842 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Bietti crystalline corneoretinal dystrophy Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 29083408, 18349091, 21232005, 20124536, 19278955) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Corneal dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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	0.066
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	3.0
DANN	Benign	0.27
DEOGEN2	Benign	0.050	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0000019	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.2	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	2.0	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.024
MPC		0.084
ClinPred		0.00089	T
GERP RS		0.98
Varity_R		0.13
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs13146272; hg19: chr4-187120211; COSMIC: COSV66505019;