rs2228545
Positions:
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The NM_001204.7(BMPR2):c.2324G>A(p.Ser775Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0297 in 1,614,166 control chromosomes in the GnomAD database, including 849 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.022 ( 54 hom., cov: 32)
Exomes 𝑓: 0.030 ( 795 hom. )
Consequence
BMPR2
NM_001204.7 missense
NM_001204.7 missense
Scores
1
2
15
Clinical Significance
Conservation
PhyloP100: 6.05
Genes affected
BMPR2 (HGNC:1078): (bone morphogenetic protein receptor type 2) This gene encodes a member of the bone morphogenetic protein (BMP) receptor family of transmembrane serine/threonine kinases. The ligands of this receptor are members of the TGF-beta superfamily. BMPs are involved in endochondral bone formation and embryogenesis. These proteins transduce their signals through the formation of heteromeric complexes of two different types of serine (threonine) kinase receptors: type I receptors of about 50-55 kD and type II receptors of about 70-80 kD. Mutations in this gene have been associated with primary pulmonary hypertension, both familial and fenfluramine-associated, and with pulmonary venoocclusive disease. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -19 ACMG points.
PP2
?
Missense variant where missense usually causes diseases, BMPR2
BP4
?
Computational evidence support a benign effect (MetaRNN=0.003867656).
BP6
?
Variant 2-202555989-G-A is Benign according to our data. Variant chr2-202555989-G-A is described in ClinVar as [Benign]. Clinvar id is 136528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-202555989-G-A is described in Lovd as [Benign]. Variant chr2-202555989-G-A is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0222 (3385/152278) while in subpopulation NFE AF= 0.0337 (2292/68022). AF 95% confidence interval is 0.0325. There are 54 homozygotes in gnomad4. There are 1584 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 3385 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BMPR2 | NM_001204.7 | c.2324G>A | p.Ser775Asn | missense_variant | 12/13 | ENST00000374580.10 | |
BMPR2 | XM_011511687.2 | c.2324G>A | p.Ser775Asn | missense_variant | 12/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BMPR2 | ENST00000374580.10 | c.2324G>A | p.Ser775Asn | missense_variant | 12/13 | 1 | NM_001204.7 | P1 | |
BMPR2 | ENST00000374574.2 | c.1586+3101G>A | intron_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0223 AC: 3387AN: 152160Hom.: 54 Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.0244 AC: 6145AN: 251390Hom.: 122 AF XY: 0.0247 AC XY: 3351AN XY: 135880
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GnomAD4 exome AF: 0.0305 AC: 44555AN: 1461888Hom.: 795 Cov.: 32 AF XY: 0.0298 AC XY: 21703AN XY: 727244
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GnomAD4 genome ? AF: 0.0222 AC: 3385AN: 152278Hom.: 54 Cov.: 32 AF XY: 0.0213 AC XY: 1584AN XY: 74452
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138
ALSPAC
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135
ESP6500AA
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ESP6500EA
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301
ExAC
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Asia WGS
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ClinVar
Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 27, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 02, 2014 | p.Ser775Asn in exon 12 of BMPR2: This variant is not expected to have clinical s ignificance because it has been identified in 3.5% (301/8600) of European Americ an chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/; dbSNP rs2228545). In addition, serine (Ser) is not conserved in mammals or evolutionarily distant species and the change to asparagine (Asn) is present in 5 mammals. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Sep 03, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Primary pulmonary hypertension Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Pulmonary hypertension, primary, 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
MutationTaster
Benign
D;N
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MPC
ClinPred
T
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