rs778361520
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS1_ModeratePM2PP2PP5
The NM_001364857.2(ADGRB2):c.4393C>T(p.Arg1465Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,872 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
ADGRB2
NM_001364857.2 missense
NM_001364857.2 missense
Scores
10
3
5
Clinical Significance
Conservation
PhyloP100: 5.53
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PS1
?
Transcript NM_001364857.2 (ADGRB2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, ADGRB2
PP5
?
Variant 1-31728621-G-A is Pathogenic according to our data. Variant chr1-31728621-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430853.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADGRB2 | NM_001364857.2 | c.4393C>T | p.Arg1465Trp | missense_variant | 30/33 | ENST00000373658.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADGRB2 | ENST00000373658.8 | c.4393C>T | p.Arg1465Trp | missense_variant | 30/33 | 5 | NM_001364857.2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152064Hom.: 0 Cov.: 31
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251462Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135910
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461808Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727206
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152064Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74264
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Progressive spastic paraparesis Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Undiagnosed Diseases Program Translational Research Laboratory, National Institutes of Health | Jul 17, 2017 | Functional studies on variant showed gain of functions compared to wild-type sequence that may explain the phenotype of the patient. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;.;T;D;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D;D;D
REVEL
Benign
Sift
Pathogenic
D;D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D
Polyphen
D;.;D;.;D;D;D
Vest4
MutPred
0.47
.;.;Loss of disorder (P = 0.0261);.;Loss of disorder (P = 0.0261);.;.;
MVP
MPC
1.7
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at