rs207482233

chr4-186201148-ATCATACAGGTCATCGCT-AGC

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP3 PP5

The NM_207352.4(CYP4V2):c.802-8_810delinsGC variant causes a splice acceptor, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYP4V2 NM_207352.4 splice_acceptor, coding_sequence, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:1
• Conservation: PhyloP100: 9.09

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.11723701 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.8, offset of -7, new splice context is: catgtgattatcattcaaAGcga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 4-186201149-TCATACAGGTCATCGCT-GC is Pathogenic according to our data. Variant chr4-186201149-TCATACAGGTCATCGCT-GC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39271.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=7, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP4V2	NM_207352.4	c.802-8_810delinsGC		splice_acceptor_variant, coding_sequence_variant, intron_variant	7/11	ENST00000378802.5
CYP4V2	XM_005262935.5	c.802-8_810delinsGC		splice_acceptor_variant, coding_sequence_variant, intron_variant	7/11
CYP4V2	XM_047450077.1	c.406-8_414delinsGC		splice_acceptor_variant, coding_sequence_variant, intron_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP4V2	ENST00000378802.5	c.802-8_810delinsGC		splice_acceptor_variant, coding_sequence_variant, intron_variant	7/11	1	NM_207352.4	P1
CYP4V2	ENST00000507209.5	n.1643-8_1651delinsGC		splice_acceptor_variant, non_coding_transcript_exon_variant, intron_variant	3/6	1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Bietti crystalline corneoretinal dystrophy Pathogenic:7

Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The CYP4V2 c.802-8_810delinsGC variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PVS1, PM3. Based on this evidence we have classified this variant as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 05, 2020	- -
Pathogenic, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 14, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	The c.802-8_810delTCATACAGGTCATCGCTinsGC variant, also described in the literature as c.802-8_810delinsG, occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.802-8_810delTCATACAGGTCATCGCTinsGC variant is the most common variant associated with Bietti crystalline dystrophy in the Japanese and Chinese populations, accounting for up to 83% of disease alleles (Park et al. 2016). The variant has been reported in at least nine studies in which it is found in at least 130 patients including 64 in a homozygous state, 65 in a compound heterozygous state and one individual in a heterozygous state in whom a second allele has not been detected (Li et al. 2004; Wada et al. 2006; Lai et al. 2007; Xiao et al. 2011; Yin et al. 2014; Meng et al. 2014; Tian et al. 2015; Park et al. 2016; Astuti et al. 2016). The variant was absent from 146 controls but is reported at a frequency of 0.00496 in the East Asian population of the 1000 Genomes Project. Due to the potential impact of splice acceptor variants and the supporting evidence from the literature, the c.802-8_810delTCATACAGGTCATCGCTinsGC variant is classified as pathogenic for Bietti crystalline dystrophy. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 06, 2017	The c.802-8_810delinsGC (NM_207352.3 c.802-8_810delinsGC) variant in CYP4V2 has been reported in over 60 homozygous and compound heterozygous individuals with B ietti crystalline dystrophy and related disorders and is the most common variant associated with this disease in East Asian populations (Wada 2005, Lin 2005, La i 2007, Yokoi 2010, Xiao 2011, Wang 2012, Chung 2013, Fu 2013, Yin 2014, Meng 20 14, Tian 2015, Astuti 2015, and Park 2016). This variant has also been reported as pathogenic in ClinVar (Variation ID#39271). This variant has been identified in 0.2% (16/8520) of East Asian chromosomes by chromosomes by the Exome Aggregat ion Consortium (ExAC, http://exac.broadinstitute.org). This variant alters the c anonical splice site, and therefore is expected to impact splicing and lead to a n absent or truncated protein. In summary, this variant meets criteria to be cla ssified as pathogenic for Bietti crystalline dystrophy and related disorders in an autosomal recessive manner based upon its biallelic occurrence in patients wi th this disease and predicted functional impact. -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Apr 12, 2012	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2022	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Reported as the most common pathogenic variant among individuals of East Asian background, accounting for 62.6% of pathogenic variants identified in one study (Zhang et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27658286, 25629076, 15042513, 23793346, 22693542, 15860296, 26865810, 24480711, 28848678, 16088246, 28763560, 30029497, 19508456, 30609409, 31054281, 31872526, 31960602, 33964374, 33857831, 33090715, 33306817, 33781268, 34068831, 30429639, 15937078) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 18, 2016	- -

Retinal dystrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Apr 23, 2019

- -

Corneal Dystrophy, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs207482233; hg19: chr4-187122303;