4-186191847-C-T

Variant names:

• chr4-186191847-C-T
• rs202148693
• NM_207352.4:c.24C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_207352.4(CYP4V2):​c.24C>T​(p.Leu8Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00038 in 1,577,370 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L8L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00084 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (4 hom.)
• Consequence: CYP4V2 NM_207352.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -2.93
• Publications: 1 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 4-186191847-C-T is Benign according to our data. Variant chr4-186191847-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 348296.
• BP7: Synonymous conserved (PhyloP=-2.93 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000841 (128/152224) while in subpopulation EAS AF = 0.015 (77/5144). AF 95% confidence interval is 0.0123. There are 2 homozygotes in GnomAd4. There are 65 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.24C>T	p.Leu8Leu	synonymous	Exon 1 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.24C>T	p.Leu8Leu	synonymous	Exon 1 of 11	ENSP00000368079.4	Q6ZWL3-1
	CYP4V2	ENST00000905173.1		c.24C>T	p.Leu8Leu	synonymous	Exon 1 of 12	ENSP00000575232.1
	CYP4V2	ENST00000905174.1		c.24C>T	p.Leu8Leu	synonymous	Exon 1 of 11	ENSP00000575233.1

Frequencies

GnomAD3 genomes AF: 0.000841 AC: 128 AN: 152110 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0149

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00107 AC: 200 AN: 186356 AF XY: 0.00112

Gnomad AFR exome AF: 0.000581

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0111

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000620

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000331 AC: 472 AN: 1425146 Hom.: 4 Cov.: 30 AF XY: 0.000348 AC XY: 246 AN XY: 706818

African (AFR) AF: 0.000400 AC: 13 AN: 32460

American (AMR) AF: 0.00 AC: 0 AN: 41492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25480

East Asian (EAS) AF: 0.00575 AC: 217 AN: 37736

South Asian (SAS) AF: 0.000909 AC: 75 AN: 82502

European-Finnish (FIN) AF: 0.0000239 AC: 1 AN: 41760

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4994

European-Non Finnish (NFE) AF: 0.0000591 AC: 65 AN: 1099670

Other (OTH) AF: 0.00171 AC: 101 AN: 59052

GnomAD4 genome AF: 0.000841 AC: 128 AN: 152224 Hom.: 2 Cov.: 33 AF XY: 0.000873 AC XY: 65 AN XY: 74440

African (AFR) AF: 0.000650 AC: 27 AN: 41562

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0150 AC: 77 AN: 5144

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67976

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.0000512 Hom.: 0

Bravo AF: 0.000729

Asia WGS AF: 0.0140 AC: 49 AN: 3468

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Bietti crystalline corneoretinal dystrophy (1)
-	1	-	Corneal dystrophy (1)
-	-	1	not provided (1)
-	-	1	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.1
DANN	Benign	0.89
PhyloP100		-2.9
PromoterAI		0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs202148693; hg19: chr4-187113001;