rs74431877

Variant names:

• chr1-31727448-G-A
• rs74431877
• NM_001364857.2:c.4730C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-31727448-G-A
• chr1-31727448-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001364857.2(ADGRB2):​c.4730C>T​(p.Pro1577Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00356 in 1,588,028 control chromosomes in the GnomAD database, including 322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1577P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0085 (91 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (231 hom.)
• Consequence: ADGRB2 NM_001364857.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.12
• Publications: 6 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015837252).
• BP6: Variant 1-31727448-G-A is Benign according to our data. Variant chr1-31727448-G-A is described in ClinVar as Benign. ClinVar VariationId is 1548756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0727 is higher than 0.05.

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.4730C>T	p.Pro1577Leu	missense	Exon 33 of 33	NP_001351786.1	O60241-1
	ADGRB2	NM_001294335.2		c.4727C>T	p.Pro1576Leu	missense	Exon 33 of 33	NP_001281264.1	O60241-2
	ADGRB2	NM_001294336.2		c.4628C>T	p.Pro1543Leu	missense	Exon 32 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.4730C>T	p.Pro1577Leu	missense	Exon 33 of 33	ENSP00000362762.3	O60241-1
	ADGRB2	ENST00000373655.6	TSL:1	c.4727C>T	p.Pro1576Leu	missense	Exon 33 of 33	ENSP00000362759.2	O60241-2
	ADGRB2	ENST00000527361.5	TSL:1	c.4628C>T	p.Pro1543Leu	missense	Exon 30 of 30	ENSP00000435397.1	O60241-4

Frequencies

GnomAD3 genomes AF: 0.00848 AC: 1290 AN: 152166 Hom.: 90 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0763

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00502

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0120 AC: 2694 AN: 224492 AF XY: 0.00923

Gnomad AFR exome AF: 0.00132

Gnomad AMR exome AF: 0.0946

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00637

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000854

Gnomad OTH exome AF: 0.00983

GnomAD4 exome AF: 0.00304 AC: 4369 AN: 1435744 Hom.: 231 Cov.: 31 AF XY: 0.00270 AC XY: 1928 AN XY: 714480

African (AFR) AF: 0.000955 AC: 30 AN: 31412

American (AMR) AF: 0.0984 AC: 3536 AN: 35950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24966

East Asian (EAS) AF: 0.0111 AC: 428 AN: 38510

South Asian (SAS) AF: 0.000207 AC: 17 AN: 82236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 0.000129 AC: 143 AN: 1104586

Other (OTH) AF: 0.00363 AC: 215 AN: 59202

GnomAD4 genome AF: 0.00848 AC: 1292 AN: 152284 Hom.: 91 Cov.: 32 AF XY: 0.00960 AC XY: 715 AN XY: 74460

African (AFR) AF: 0.00128 AC: 53 AN: 41562

American (AMR) AF: 0.0764 AC: 1169 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00503 AC: 26 AN: 5168

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68020

Other (OTH) AF: 0.0156 AC: 33 AN: 2112

Alfa AF: 0.00264 Hom.: 56

Bravo AF: 0.0133

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0106 AC: 1283

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.57
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.0082	T
Eigen	Benign	-0.087
Eigen_PC	Benign	-0.041
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.92	T
PhyloP100		4.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.093
Sift	Benign	0.14	T
Sift4G	Benign	0.26	T
Polyphen		0.84	P
Vest4		0.15
MPC		0.75
ClinPred		0.020	T
GERP RS		4.0
Varity_R		0.075
gMVP		0.24
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs74431877; hg19: chr1-32193049;