2-178324216-G-A

Variant names:

• chr2-178324216-G-A
• rs138286651
• NM_032523.4:c.142G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_032523.4(OSBPL6):​c.142G>A​(p.Glu48Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000532 in 1,582,500 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E48Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (2 hom.)
• Consequence: OSBPL6 NM_032523.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.95
• Publications: 2 publications found

Genes affected

OSBPL6 (HGNC:16388): (oxysterol binding protein like 6) 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. Transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.057922333).
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OSBPL6	NM_032523.4	c.142G>A	p.Glu48Lys	missense_variant	Exon 4 of 25	ENST00000190611.9	NP_115912.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OSBPL6	ENST00000190611.9	c.142G>A	p.Glu48Lys	missense_variant	Exon 4 of 25	1	NM_032523.4	ENSP00000190611.4

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000281 AC: 63 AN: 223930 AF XY: 0.000208

Gnomad AFR exome AF: 0.000211

Gnomad AMR exome AF: 0.000152

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000497

Gnomad NFE exome AF: 0.000508

Gnomad OTH exome AF: 0.000534

GnomAD4 exome AF: 0.000562 AC: 804 AN: 1430314 Hom.: 2 Cov.: 30 AF XY: 0.000503 AC XY: 356 AN XY: 708316

African (AFR) AF: 0.000121 AC: 4 AN: 33128

American (AMR) AF: 0.000161 AC: 7 AN: 43344

Ashkenazi Jewish (ASJ) AF: 0.0000394 AC: 1 AN: 25360

East Asian (EAS) AF: 0.00 AC: 0 AN: 39134

South Asian (SAS) AF: 0.000158 AC: 13 AN: 82428

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.000684 AC: 746 AN: 1090544

Other (OTH) AF: 0.000543 AC: 32 AN: 58900

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74398

African (AFR) AF: 0.0000723 AC: 3 AN: 41508

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.000491 Hom.: 1

Bravo AF: 0.000302

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000232 AC: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.142G>A (p.E48K) alteration is located in exon 4 (coding exon 2) of the OSBPL6 gene. This alteration results from a G to A substitution at nucleotide position 142, causing the glutamic acid (E) at amino acid position 48 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	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	.;.;.;.;T;.;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;.;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.058	T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N;N;N;N;N;N;.
PhyloP100		6.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.71	N;N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0080	D;D;D;D;D;D;D
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.20	B;B;.;B;B;B;B
Vest4		0.42
MVP		0.12
MPC		0.36
ClinPred		0.016	T
GERP RS		6.0
Varity_R		0.21
gMVP		0.34
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs138286651; hg19: chr2-179188943; COSMIC: COSV51911639;