OCA2 p.Phe809Leu

Variant names:

• chr15-27844964-A-T
• NM_000275.3:c.2427T>A
• OCA2 p.Phe809Leu

Your query was ambiguous. Multiple possible variants found:

• chr15-27844964-A-T
• chr15-27844964-A-C
• chr15-27844966-A-G
• chr15-27844964-AAA-GAG
• chr15-27844964-AAA-TAG
• chr15-27844964-AAA-CAG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000275.3(OCA2):​c.2427T>A​(p.Phe809Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F809I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: OCA2 NM_000275.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.91
• Publications: 0 publications found

Genes affected

OCA2 (HGNC:8101): (OCA2 melanosomal transmembrane protein) This gene encodes the human homolog of the mouse p (pink-eyed dilution) gene. The encoded protein is believed to be an integral membrane protein involved in small molecule transport, specifically tyrosine, which is a precursor to melanin synthesis. It is involved in mammalian pigmentation, where it may control skin color variation and act as a determinant of brown or blue eye color. Mutations in this gene result in type 2 oculocutaneous albinism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

OCA2 Gene-Disease associations (from GenCC):

• oculocutaneous albinism type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_000275.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-27844966-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 195725.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000275.3. 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
	OCA2	NM_000275.3	MANE Select	c.2427T>A	p.Phe809Leu	missense	Exon 23 of 24	NP_000266.2	Q04671-1
	OCA2	NM_001300984.2		c.2355T>A	p.Phe785Leu	missense	Exon 22 of 23	NP_001287913.1	Q04671-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCA2	ENST00000354638.8	TSL:1 MANE Select	c.2427T>A	p.Phe809Leu	missense	Exon 23 of 24	ENSP00000346659.3	Q04671-1
	OCA2	ENST00000353809.9	TSL:1	c.2355T>A	p.Phe785Leu	missense	Exon 22 of 23	ENSP00000261276.8	Q04671-2
	OCA2	ENST00000910120.1		c.2673T>A	p.Phe891Leu	missense	Exon 25 of 26	ENSP00000580179.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		1.9
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Varity_R		0.61
gMVP		0.94

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr15-28090110;