1-31727509-G-A

Variant names:

• chr1-31727509-G-A
• rs769490381
• NM_001364857.2:c.4669C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001364857.2(ADGRB2):​c.4669C>T​(p.Pro1557Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1557A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ADGRB2 NM_001364857.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.586

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

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=0.06422776).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADGRB2	NM_001364857.2	c.4669C>T	p.Pro1557Ser	missense_variant	Exon 33 of 33	ENST00000373658.8	NP_001351786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADGRB2	ENST00000373658.8	c.4669C>T	p.Pro1557Ser	missense_variant	Exon 33 of 33	5	NM_001364857.2	ENSP00000362762.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000430 AC: 1 AN: 232700 Hom.: 0 AF XY: 0.00000790 AC XY: 1 AN XY: 126628

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000345

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445004 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719154

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000258

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.016	T;T;.;T;T;.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.064	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N
REVEL	Benign	0.047
Sift	Benign	0.48	T;T;T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T;T;T
Polyphen		0.0	.;.;B;.;B;B;B
Vest4		0.068
MutPred		0.16		.;.;.;.;Loss of catalytic residue at P1556 (P = 0.0193);.;.;
MVP		0.043
MPC		0.69
ClinPred		0.15	T
GERP RS		3.2
Varity_R		0.063
gMVP		0.27

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: rs769490381; hg19: chr1-32193110;