rs41263977

Variant names:

• chr1-31727584-G-A
• rs41263977
• NM_001364857.2:c.4594C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001364857.2(ADGRB2):​c.4594C>T​(p.Arg1532Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00903 in 1,548,822 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0093 (82 hom.)
• Consequence: ADGRB2 NM_001364857.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.96
• Publications: 7 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005131185).
• BP6: Variant 1-31727584-G-A is Benign according to our data. Variant chr1-31727584-G-A is described in ClinVar as Benign. ClinVar VariationId is 1598588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 gene

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.4594C>T	p.Arg1532Cys	missense	Exon 33 of 33	NP_001351786.1	O60241-1
	ADGRB2	NM_001294335.2		c.4591C>T	p.Arg1531Cys	missense	Exon 33 of 33	NP_001281264.1	O60241-2
	ADGRB2	NM_001294336.2		c.4492C>T	p.Arg1498Cys	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.4594C>T	p.Arg1532Cys	missense	Exon 33 of 33	ENSP00000362762.3	O60241-1
	ADGRB2	ENST00000373655.6	TSL:1	c.4591C>T	p.Arg1531Cys	missense	Exon 33 of 33	ENSP00000362759.2	O60241-2
	ADGRB2	ENST00000527361.5	TSL:1	c.4492C>T	p.Arg1498Cys	missense	Exon 30 of 30	ENSP00000435397.1	O60241-4

Frequencies

GnomAD3 genomes AF: 0.00687 AC: 1044 AN: 152018 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.0240

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00968 AC: 1751 AN: 180960 AF XY: 0.00934

Gnomad AFR exome AF: 0.00164

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.000181

Gnomad EAS exome AF: 0.0000723

Gnomad FIN exome AF: 0.0269

Gnomad NFE exome AF: 0.0133

Gnomad OTH exome AF: 0.00892

GnomAD4 exome AF: 0.00926 AC: 12939 AN: 1396686 Hom.: 82 Cov.: 31 AF XY: 0.00893 AC XY: 6177 AN XY: 691402

African (AFR) AF: 0.00119 AC: 36 AN: 30204

American (AMR) AF: 0.00133 AC: 41 AN: 30848

Ashkenazi Jewish (ASJ) AF: 0.000179 AC: 4 AN: 22342

East Asian (EAS) AF: 0.000133 AC: 5 AN: 37608

South Asian (SAS) AF: 0.00135 AC: 101 AN: 74692

European-Finnish (FIN) AF: 0.0264 AC: 1358 AN: 51460

Middle Eastern (MID) AF: 0.000395 AC: 2 AN: 5058

European-Non Finnish (NFE) AF: 0.0101 AC: 10964 AN: 1086990

Other (OTH) AF: 0.00745 AC: 428 AN: 57484

GnomAD4 genome AF: 0.00686 AC: 1044 AN: 152136 Hom.: 3 Cov.: 32 AF XY: 0.00721 AC XY: 536 AN XY: 74366

African (AFR) AF: 0.00137 AC: 57 AN: 41520

American (AMR) AF: 0.00229 AC: 35 AN: 15296

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

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5144

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4818

European-Finnish (FIN) AF: 0.0240 AC: 254 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0100 AC: 680 AN: 67970

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00848 Hom.: 20

Bravo AF: 0.00497

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00895 AC: 77

ExAC AF: 0.00986 AC: 1196

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.97	D
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.77	T
PhyloP100		4.0
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.12
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.011	D
Polyphen		0.95	P
Vest4		0.24
MVP		0.15
MPC		1.1
ClinPred		0.021	T
GERP RS		3.3
Varity_R		0.16
gMVP		0.25
Mutation Taster		=86/14	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: rs41263977; hg19: chr1-32193185; COSMIC: COSV108751440;