rs34731820

chr15-27990583-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_000275.3(OCA2):c.1109T>C(p.Ile370Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000613 in 1,614,014 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (5 hom.)
• Consequence: OCA2 NM_000275.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 6.22

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 Benign. Variant got -7 ACMG points.

• PM1: In a transmembrane_region Helical (size 16) in uniprot entity P_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000275.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.01856479).
• BP6: Variant 15-27990583-A-G is Benign according to our data. Variant chr15-27990583-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 419971.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=1, Benign=1}.
• BS2: High Homozygotes in GnomAd at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OCA2	NM_000275.3	c.1109T>C	p.Ile370Thr	missense_variant	10/24	ENST00000354638.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OCA2	ENST00000354638.8	c.1109T>C	p.Ile370Thr	missense_variant	10/24	1	NM_000275.3	P1
OCA2	ENST00000353809.9	c.1045-917T>C		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00334 AC: 508 AN: 152206 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000868 AC: 218 AN: 251172 Hom.: 0 AF XY: 0.000604 AC XY: 82 AN XY: 135756

Gnomad AFR exome AF: 0.0126

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000328 AC: 480 AN: 1461690 Hom.: 5 Cov.: 30 AF XY: 0.000301 AC XY: 219 AN XY: 727152

Gnomad4 AFR exome AF: 0.0125

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.00335 AC: 510 AN: 152324 Hom.: 4 Cov.: 32 AF XY: 0.00311 AC XY: 232 AN XY: 74492

Gnomad4 AFR AF: 0.0119

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000604 Hom.: 0

Bravo AF: 0.00373

ExAC AF: 0.000997 AC: 121

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tyrosinase-positive oculocutaneous albinism Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 12, 2017	The OCA2 c.1109T>C (p.Ile370Thr) missense variant has been reported in one study in which it was found in a compound heterozygous state with a second missense variant in one individual with an unusual hypopigmentation type, and in a heterozygous state in another individual with a skin color resembling that of rufus oculocutaneous albinism, in whom a second variant was not detected (Kerr et al. 2000). The Ile370 residue is conserved. Control data are unavailable for this variant, which is reported at a frequency of 0.025253 in the Esan in Nigeria population of the 1000 Genomes Project. Based on the evidence, the p.Ile370Thr variant is classified as a variant of uncertain significance but suspicious for pathogenicity for oculocutaneous albinism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 26, 2017	The I370T variant in the OCA2 gene has been reported previously in two unrelated individuals of African descent with an unusual hypopigmentation phenotype suggestive of oculocutaneous albinism (OCA). The I370T variant was reported along with a second variant in an individual with light brown eyes and yellow-ish white colored hair. The second individual was heterozygous for the I370T variant, with no second variant identified, and had reddish-brown colored skin (Kerr et al., 2000). The I370T variant is observed in 114/10360 (1.1%) alleles from individuals of African background in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016). The I370T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret I370T as a variant of uncertain significance. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 20, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	18
Dann	Benign	0.91
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.088
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.019	T
MetaSVM	Uncertain	-0.081	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	0.86	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.0060	B
Vest4		0.85
MVP		0.96
MPC		0.14
ClinPred		0.042	T
GERP RS		4.8
Varity_R		0.27
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs34731820; hg19: chr15-28235729;