11-132436127-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001012393.5(OPCML):c.875C>A(p.Thr292Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: OPCML NM_001012393.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.81

Genes affected

OPCML (HGNC:8143): (opioid binding protein/cell adhesion molecule like) This gene encodes a member of the IgLON subfamily in the immunoglobulin protein superfamily of proteins. The encoded preprotein is proteolytically processed to generate the mature protein. This protein is localized in the plasma membrane and may have an accessory role in opioid receptor function. This gene has an ortholog in rat and bovine. The opioid binding-cell adhesion molecule encoded by the rat gene binds opioid alkaloids in the presence of acidic lipids, exhibits selectivity for mu ligands and acts as a GPI-anchored protein. Since the encoded protein is highly conserved in species during evolution, it may have a fundamental role in mammalian systems. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPCML	NM_001012393.5	c.875C>A	p.Thr292Lys	missense_variant	7/8	ENST00000524381.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPCML	ENST00000524381.6	c.875C>A	p.Thr292Lys	missense_variant	7/8	1	NM_001012393.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2024

The c.896C>A (p.T299K) alteration is located in exon 6 (coding exon 6) of the OPCML gene. This alteration results from a C to A substitution at nucleotide position 896, causing the threonine (T) at amino acid position 299 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
Cadd	Uncertain	24
Dann	Benign	0.97
DEOGEN2	Benign	0.13	T;T;.;.;.
Eigen	Benign	-0.085
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.50	D;D;D;D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.6	L;L;L;.;.
MutationTaster	Benign	0.59	N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	N;.;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.051	T;.;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T
Polyphen		0.063	B;B;.;.;.
Vest4		0.49
MutPred		0.59		Gain of ubiquitination at T299 (P = 0.0203);Gain of ubiquitination at T299 (P = 0.0203);Gain of ubiquitination at T299 (P = 0.0203);.;.;
MVP		0.57
MPC		0.97
ClinPred		0.84	D
GERP RS		5.0
Varity_R		0.32
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs377189862; hg19: chr11-132306021;