chr20-62260019-G-A

Variant names:

• chr20-62260019-G-A
• rs79783838
• NM_144498.4:c.76G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144498.4(OSBPL2):​c.76G>A​(p.Ala26Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,613,896 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (35 hom.)
• Consequence: OSBPL2 NM_144498.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.508
• Publications: 6 publications found

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]

OSBPL2 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 67

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021491945).
• BP6: Variant 20-62260019-G-A is Benign according to our data. Variant chr20-62260019-G-A is described in ClinVar as Benign. ClinVar VariationId is 667053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0107 (1626/152248) while in subpopulation AFR AF = 0.0375 (1558/41542). AF 95% confidence interval is 0.036. There are 38 homozygotes in GnomAd4. There are 776 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1626 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144498.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSBPL2	NM_144498.4	MANE Select	c.76G>A	p.Ala26Thr	missense	Exon 3 of 14	NP_653081.1	Q9H1P3-1
	OSBPL2	NM_014835.5		c.40G>A	p.Ala14Thr	missense splice_region	Exon 3 of 14	NP_055650.1	Q9H1P3-2
	OSBPL2	NM_001363878.2		c.-291G>A		5_prime_UTR	Exon 3 of 15	NP_001350807.1	A0A2R8YDU7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSBPL2	ENST00000313733.9	TSL:1 MANE Select	c.76G>A	p.Ala26Thr	missense	Exon 3 of 14	ENSP00000316649.3	Q9H1P3-1
	OSBPL2	ENST00000358053.3	TSL:1	c.40G>A	p.Ala14Thr	missense splice_region	Exon 3 of 14	ENSP00000350755.2	Q9H1P3-2
	OSBPL2	ENST00000865094.1		c.76G>A	p.Ala26Thr	missense	Exon 3 of 14	ENSP00000535153.1

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1619 AN: 152130 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.0374

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00268 AC: 675 AN: 251410 AF XY: 0.00204

Gnomad AFR exome AF: 0.0372

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00110 AC: 1602 AN: 1461648 Hom.: 35 Cov.: 30 AF XY: 0.000968 AC XY: 704 AN XY: 727142

African (AFR) AF: 0.0382 AC: 1280 AN: 33470

American (AMR) AF: 0.00195 AC: 87 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1111818

Other (OTH) AF: 0.00286 AC: 173 AN: 60384

GnomAD4 genome AF: 0.0107 AC: 1626 AN: 152248 Hom.: 38 Cov.: 32 AF XY: 0.0104 AC XY: 776 AN XY: 74434

African (AFR) AF: 0.0375 AC: 1558 AN: 41542

American (AMR) AF: 0.00340 AC: 52 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00407 Hom.: 22

Bravo AF: 0.0121

ESP6500AA AF: 0.0352 AC: 155

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00310 AC: 376

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.70
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.86	L
PhyloP100		0.51
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.033
Sift	Benign	0.34	T
Sift4G	Benign	0.44	T
Polyphen		0.0010	B
Vest4		0.093
MVP		0.13
MPC		0.58
ClinPred		0.0026	T
GERP RS		-0.91
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.028
gMVP		0.22
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs79783838; hg19: chr20-60835075;