rs199476183

Positions:

• chr4-186208863-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_207352.4(CYP4V2):​c.1091-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CYP4V2 NM_207352.4 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.15

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08491762 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.9, offset of 24, new splice context is: gtctgaccgtcccgctacAGtag. Cryptic site results in inframe 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
• PP5: Variant 4-186208863-A-G is Pathogenic according to our data. Variant chr4-186208863-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-186208863-A-G is described in Lovd as [Pathogenic]. Variant chr4-186208863-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP4V2	NM_207352.4	c.1091-2A>G		splice_acceptor_variant		ENST00000378802.5	NP_997235.3
CYP4V2	XM_005262935.5	c.1091-2A>G		splice_acceptor_variant			XP_005262992.1
CYP4V2	XM_047450077.1	c.695-2A>G		splice_acceptor_variant			XP_047306033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP4V2	ENST00000378802.5	c.1091-2A>G		splice_acceptor_variant		1	NM_207352.4	ENSP00000368079	P1
CYP4V2	ENST00000502665.1	n.326-2A>G		splice_acceptor_variant, non_coding_transcript_variant		1
CYP4V2	ENST00000507209.5	n.5789-2A>G		splice_acceptor_variant, non_coding_transcript_variant		1
CYP4V2	ENST00000513354.5	n.181-2A>G		splice_acceptor_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251494 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461888 Hom.: 0 Cov.: 38 AF XY: 0.00000963 AC XY: 7 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000416

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bietti crystalline corneoretinal dystrophy Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The CYP4V2 c.1091-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. Across a selection of available literature, the c.1091-2A>G variant has been identified in 30 individuals with retinal atrophy, Bietti crystalline dystrophy, or retinitis pigmentosa, including in a homozygous state in five individuals and in a compound heterozygous state in 25 individuals. In addition, it was reported in a heterozygous state in five unaffected family members (Li et al. 2004; Xiao et al. 2011; Wang et al. 2012; Fu et al. 2013; Meng et al. 2014). The c.1091-2A>G variant was absent from 196 controls and is reported at a frequency of 0.00035 in the East Asian population of the Exome Aggregation Consortium. Based on the potential impact of splice acceptor variants and evidence from the literature, the c.1091-2A>G variant is classified as pathogenic for Bietti crystalline dystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 14, 2013	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Apr 12, 2012	- -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The CYP4V2 c.1091-2A>G 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: PVS1, PM2, PM3. Based on this evidence we have classified this variant as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 10, 2023

This sequence change affects an acceptor splice site in intron 8 of the CYP4V2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CYP4V2 are known to be pathogenic (PMID: 15042513, 25118264). This variant is present in population databases (rs199476183, gnomAD 0.06%). Disruption of this splice site has been observed in individual(s) with Bietti crystalline dystrophy and retinitis pigmentosa (PMID: 15042513). This variant is also known as IVS8-2A>G. ClinVar contains an entry for this variant (Variation ID: 2191). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy Pathogenic:1

Likely pathogenic, 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_addAF	Pathogenic	0.38	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	30
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.49		Position offset: -25
DS_AL_spliceai		0.98		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476183; hg19: chr4-187130017;