15-27871170-G-C

Variant names:

• chr15-27871170-G-C
• NM_000275.3:c.2228C>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000275.3(OCA2):​c.2228C>G​(p.Pro743Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in Lovd as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P743L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: OCA2 NM_000275.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.11

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 22) in uniprot entity P_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chr15-27871170-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 15-27871170-G-C is Pathogenic according to our data. Variant chr15-27871170-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OCA2	NM_000275.3	c.2228C>G	p.Pro743Arg	missense_variant	Exon 21 of 24	ENST00000354638.8	NP_000266.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OCA2	ENST00000354638.8	c.2228C>G	p.Pro743Arg	missense_variant	Exon 21 of 24	1	NM_000275.3	ENSP00000346659.3
OCA2	ENST00000353809.9	c.2156C>G	p.Pro719Arg	missense_variant	Exon 20 of 23	1		ENSP00000261276.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461408 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727032

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	.;H
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-8.0	D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.98		.;Gain of methylation at P743 (P = 0.0214);
MVP		1.0
MPC		0.50
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.83
gMVP		0.99

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-28116316;