chr4-186201149-TCATACAGGTCATCGCT-GC

Variant names:

• chr4-186201149-TCATACAGGTCATCGCT-GC
• rs207482233
• NM_207352.4:c.802-8_810delTCATACAGGTCATCGCTinsGC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_207352.4(CYP4V2):​c.802-8_810delTCATACAGGTCATCGCTinsGC​(p.Val268_Ala270del) variant causes a splice acceptor, conservative inframe deletion, splice region, synonymous, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CYP4V2 NM_207352.4 splice_acceptor, conservative_inframe_deletion, splice_region, synonymous, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 9.09
• Publications: 16 publications found

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]

CYP4V2 Gene-Disease associations (from GenCC):

• Bietti crystalline corneoretinal dystrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, G2P, ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.117870726 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.
• PP5: Variant 4-186201149-TCATACAGGTCATCGCT-GC is Pathogenic according to our data. Variant chr4-186201149-TCATACAGGTCATCGCT-GC is described in ClinVar as Pathogenic. ClinVar VariationId is 39271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207352.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP4V2	NM_207352.4	MANE Select	c.802-8_810delTCATACAGGTCATCGCTinsGC	p.Val268_Ala270del	splice_acceptor conservative_inframe_deletion splice_region synonymous intron	Exon 7 of 11	NP_997235.3	Q6ZWL3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP4V2	ENST00000378802.5	TSL:1 MANE Select	c.802-8_810delTCATACAGGTCATCGCTinsGC	p.Val268_Ala270del	splice_acceptor conservative_inframe_deletion splice_region synonymous intron	Exon 7 of 11	ENSP00000368079.4	Q6ZWL3-1
	CYP4V2	ENST00000507209.5	TSL:1	n.1643-8_1651delTCATACAGGTCATCGCTinsGC		splice_acceptor splice_region intron non_coding_transcript_exon	Exon 3 of 6
	CYP4V2	ENST00000905173.1		c.802-8_810delTCATACAGGTCATCGCTinsGC	p.Val268_Ala270del	splice_acceptor conservative_inframe_deletion splice_region synonymous intron	Exon 7 of 12	ENSP00000575232.1

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Bietti crystalline corneoretinal dystrophy (9)
2	-	-	not provided (2)
2	-	-	Retinal dystrophy (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.1
Mutation Taster		=13/187	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs207482233; hg19: chr4-187122303;