Variant 1-31728038-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001364857.2(ADGRB2):c.4559G>A(p.Arg1520Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,577,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ADGRB2
NM_001364857.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.270

Variant links:

Genes affected

ADGRB2 (HGNC:944): (adhesion G protein-coupled receptor B2) This gene encodes a a seven-span transmembrane protein that is thought to be a member of the secretin receptor family. The encoded protein is a brain-specific inhibitor of angiogenesis. The mature peptide may be further cleaved into additional products (PMID:20367554). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ADGRB2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.043979317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADGRB2	NM_001364857.2 linkuse as main transcript	c.4559G>A	p.Arg1520Gln	missense_variant	32/33	ENST00000373658.8	NP_001351786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADGRB2	ENST00000373658.8 linkuse as main transcript	c.4559G>A	p.Arg1520Gln	missense_variant	32/33	5	NM_001364857.2	ENSP00000362762		O60241-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000105

AC:

AN:

1425122

Hom.:

Cov.:

AF XY:

0.00000566

AC XY:

AN XY:

706766

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000392

Gnomad4 EAS exome

AF:

0.0000262

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000109

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000250

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 08, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with ADGRB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1486 of the ADGRB2 protein (p.Arg1486Gln). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0072

T;.;T;.

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.82

T;T;T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.044

T;T;T;T

MetaSVM

Benign

-0.99

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.010

N;N;N;N

REVEL

Benign

0.030

Sift

Benign

0.30

T;T;T;T

Sift4G

Benign

0.47

T;T;T;T

Polyphen

0.0010

B;B;B;B

Vest4

0.17

MutPred

0.16

.;.;Loss of MoRF binding (P = 0.0331);.;

MVP

0.043

MPC

0.79

ClinPred

0.28

GERP RS

3.9

Varity_R

0.10

gMVP

0.091

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over