rs3736456

Positions:

• chr4-186201201-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000378802.5(CYP4V2):​c.846T>C​(p.Cys282=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0752 in 1,614,064 control chromosomes in the GnomAD database, including 7,715 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (893 hom., cov: 31)
  • Exomes 𝑓: 0.074 (6822 hom.)
• Consequence: CYP4V2 ENST00000378802.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.55

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 4-186201201-T-C is Benign according to our data. Variant chr4-186201201-T-C is described in ClinVar as [Benign]. Clinvar id is 166977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186201201-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP4V2	NM_207352.4	c.846T>C	p.Cys282=	synonymous_variant	7/11	ENST00000378802.5	NP_997235.3
CYP4V2	XM_005262935.5	c.846T>C	p.Cys282=	synonymous_variant	7/11		XP_005262992.1
CYP4V2	XM_047450077.1	c.450T>C	p.Cys150=	synonymous_variant	5/9		XP_047306033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP4V2	ENST00000378802.5	c.846T>C	p.Cys282=	synonymous_variant	7/11	1	NM_207352.4	ENSP00000368079	P1
CYP4V2	ENST00000507209.5	n.1687T>C		non_coding_transcript_exon_variant	3/6	1

Frequencies

GnomAD3 genomes AF: 0.0853 AC: 12975 AN: 152094 Hom.: 896 Cov.: 31

Gnomad AFR AF: 0.0629

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.334

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.0942

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0529

Gnomad OTH AF: 0.0974

GnomAD3 exomes AF: 0.123 AC: 30982 AN: 251462 Hom.: 2992 AF XY: 0.120 AC XY: 16293 AN XY: 135908

Gnomad AFR exome AF: 0.0626

Gnomad AMR exome AF: 0.236

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.348

Gnomad SAS exome AF: 0.162

Gnomad FIN exome AF: 0.0954

Gnomad NFE exome AF: 0.0554

Gnomad OTH exome AF: 0.122

GnomAD4 exome AF: 0.0742 AC: 108428 AN: 1461852 Hom.: 6822 Cov.: 34 AF XY: 0.0763 AC XY: 55467 AN XY: 727234

Gnomad4 AFR exome AF: 0.0646

Gnomad4 AMR exome AF: 0.229

Gnomad4 ASJ exome AF: 0.133

Gnomad4 EAS exome AF: 0.326

Gnomad4 SAS exome AF: 0.160

Gnomad4 FIN exome AF: 0.0900

Gnomad4 NFE exome AF: 0.0491

Gnomad4 OTH exome AF: 0.0924

GnomAD4 genome AF: 0.0853 AC: 12983 AN: 152212 Hom.: 893 Cov.: 31 AF XY: 0.0907 AC XY: 6746 AN XY: 74406

Gnomad4 AFR AF: 0.0630

Gnomad4 AMR AF: 0.161

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.334

Gnomad4 SAS AF: 0.167

Gnomad4 FIN AF: 0.0942

Gnomad4 NFE AF: 0.0529

Gnomad4 OTH AF: 0.0959

Alfa AF: 0.0654 Hom.: 672

Bravo AF: 0.0926

Asia WGS AF: 0.202 AC: 702 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Eurofins Ntd Llc (ga)	Apr 28, 2014	- -

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	- -
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

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. -

Bietti crystalline corneoretinal 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
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.17
DANN	Benign	0.26

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: rs3736456; hg19: chr4-187122355; COSMIC: COSV66505958; COSMIC: COSV66505958;