chr1-31728039-G-A

Variant names:

• chr1-31728039-G-A
• rs760122373
• NM_001364857.2:c.4558C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001364857.2(ADGRB2):​c.4558C>T​(p.Arg1520Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,579,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1520Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000091 (0 hom.)
• Consequence: ADGRB2 NM_001364857.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.207
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048320472).
• BP6: Variant 1-31728039-G-A is Benign according to our data. Variant chr1-31728039-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3496674.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364857.2. 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
	ADGRB2	NM_001364857.2	MANE Select	c.4558C>T	p.Arg1520Trp	missense	Exon 32 of 33	NP_001351786.1	O60241-1
	ADGRB2	NM_001294335.2		c.4555C>T	p.Arg1519Trp	missense	Exon 32 of 33	NP_001281264.1	O60241-2
	ADGRB2	NM_001294336.2		c.4456C>T	p.Arg1486Trp	missense	Exon 31 of 32	NP_001281265.1	O60241-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADGRB2	ENST00000373658.8	TSL:5 MANE Select	c.4558C>T	p.Arg1520Trp	missense	Exon 32 of 33	ENSP00000362762.3	O60241-1
	ADGRB2	ENST00000373655.6	TSL:1	c.4555C>T	p.Arg1519Trp	missense	Exon 32 of 33	ENSP00000362759.2	O60241-2
	ADGRB2	ENST00000527361.5	TSL:1	c.4456C>T	p.Arg1486Trp	missense	Exon 29 of 30	ENSP00000435397.1	O60241-4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD2 exomes AF: 0.0000152 AC: 3 AN: 196938 AF XY: 0.0000187

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000337

Gnomad ASJ exome AF: 0.000110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000911 AC: 13 AN: 1427120 Hom.: 0 Cov.: 30 AF XY: 0.00000848 AC XY: 6 AN XY: 707898

African (AFR) AF: 0.0000304 AC: 1 AN: 32896

American (AMR) AF: 0.0000247 AC: 1 AN: 40542

Ashkenazi Jewish (ASJ) AF: 0.0000392 AC: 1 AN: 25542

East Asian (EAS) AF: 0.00 AC: 0 AN: 38248

South Asian (SAS) AF: 0.0000242 AC: 2 AN: 82674

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5214

European-Non Finnish (NFE) AF: 0.00000728 AC: 8 AN: 1098412

Other (OTH) AF: 0.00 AC: 0 AN: 59232

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152022 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74248

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.000262 AC: 4 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000416 AC: 5

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0090	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.21
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.059
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.059	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.21		Loss of phosphorylation at S1521 (P = 0.077)
MVP		0.043
MPC		0.94
ClinPred		0.23	T
GERP RS		-3.5
Varity_R		0.071
gMVP		0.15
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs760122373; hg19: chr1-32193640;