20-62260005-G-C

Variant names:

• chr20-62260005-G-C
• rs1202357119
• NM_144498.4:c.62G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144498.4(OSBPL2):​c.62G>C​(p.Gly21Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: OSBPL2 NM_144498.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.25

Genes affected

OSBPL2 (HGNC:15761): (oxysterol binding protein like 2) This gene encodes a member of the oxysterol-binding protein (OSBP) family, a group of intracellular lipid receptors. Most members contain an N-terminal pleckstrin homology domain and a highly conserved C-terminal OSBP-like sterol-binding domain, although the encoded protein contains only the sterol-binding domain. In vitro studies have shown that the encoded protein can bind strongly to phosphatic acid and weakly to phosphatidylinositol 3-phosphate, but cannot bind to 25-hydroxycholesterol. The protein associates with the Golgi apparatus. Transcript variants encoding different isoforms have been described. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17371956).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OSBPL2	NM_144498.4	c.62G>C	p.Gly21Ala	missense_variant	Exon 3 of 14	ENST00000313733.9	NP_653081.1
OSBPL2	NM_001363878.2	c.-305G>C		5_prime_UTR_variant	Exon 3 of 15		NP_001350807.1
OSBPL2	NM_014835.5	c.38-12G>C		intron_variant	Intron 2 of 13		NP_055650.1
OSBPL2	NM_001278649.3	c.-184-3611G>C		intron_variant	Intron 2 of 12		NP_001265578.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OSBPL2	ENST00000313733.9	c.62G>C	p.Gly21Ala	missense_variant	Exon 3 of 14	1	NM_144498.4	ENSP00000316649.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251358 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461704 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 21 of the OSBPL2 protein (p.Gly21Ala). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with OSBPL2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.025	.;.;T;.;T;.;T
Eigen	Benign	-0.068
Eigen_PC	Benign	0.086
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.68	T;T;.;D;.;T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.17	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	.;.;M;.;M;.;M
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.58	.;.;N;.;.;.;.
REVEL	Benign	0.10
Sift	Benign	0.061	.;.;T;.;.;.;.
Sift4G	Benign	0.36	.;T;T;.;.;.;.
Polyphen		0.038	.;.;B;.;B;.;B
Vest4		0.43
MutPred		0.11		Loss of glycosylation at S20 (P = 0.0493);Loss of glycosylation at S20 (P = 0.0493);Loss of glycosylation at S20 (P = 0.0493);Loss of glycosylation at S20 (P = 0.0493);Loss of glycosylation at S20 (P = 0.0493);Loss of glycosylation at S20 (P = 0.0493);Loss of glycosylation at S20 (P = 0.0493);
MVP		0.27
MPC		1.5
ClinPred		0.69	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.085
gMVP		0.37

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: rs1202357119; hg19: chr20-60835061;