rs1060502583

Variant names:

• chr2-202552811-A-C
• rs1060502583
• NM_001204.7:c.1509A>C

Your query was ambiguous. Multiple possible variants found:

• chr2-202552811-A-C
• chr2-202552811-A-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS3

This summary comes from the ClinGen Evidence Repository: The NM_001204.7(BMPR2) c.1509A>C variant is a missense variant predicted to cause substitution of glutamate by aspartate at amino acid 503 (p.Glu503Asp). The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.0001105 (1/9046 alleles) in East Asian population, which is higher than the ClinGen PH VCEP threshold (<0.01%) for PM2 but lower than the threshold (>0.1%) for BS1. Therefore, this variant does not meet either of these population criteria. The computational predictor REVEL gives a score of 0.662, which is neither above nor below the thresholds predicting a damaging or benign impact on BMPR2 function. Luciferase assay data indicated that variant transcriptional activity was comparable to wild-type, indicating no deleterious effect (BS3; PMID:18321866). The p.Glu503Asp (p.E503D) mutant also shows normal localization to the plasma membrane (PMID:25688877) and no effect on cell viability (PMID:30809644). In summary, this variant meets the criteria to be classified as likely benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS3. (VCEP specifications version 1.1, 1/18/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA16610570/MONDO:0015924/125

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:2 B:2
• Conservation: PhyloP100: 1.92
• Publications: 3 publications found

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]

BMPR2 Gene-Disease associations (from GenCC):

• pulmonary arterial hypertension

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pulmonary hypertension, primary, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• heritable pulmonary arterial hypertension

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Specifications for BMPR2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204.7. 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
	BMPR2	NM_001204.7	MANE Select	c.1509A>C	p.Glu503Asp	missense	Exon 11 of 13	NP_001195.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR2	ENST00000374580.10	TSL:1 MANE Select	c.1509A>C	p.Glu503Asp	missense	Exon 11 of 13	ENSP00000363708.4	Q13873-1
	BMPR2	ENST00000374574.2	TSL:2	c.1509A>C	p.Glu503Asp	missense	Exon 11 of 12	ENSP00000363702.2	Q13873-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251488 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	Pulmonary arterial hypertension associated with congenital heart disease (2)
-	-	1	Primary pulmonary hypertension (1)
-	-	1	Pulmonary arterial hypertension (1)
-	1	-	Pulmonary venoocclusive disease 1;C4552070:Pulmonary hypertension, primary, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.010
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.77	N
PhyloP100		1.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.037	D
Polyphen		0.53	P
Vest4		0.79
MutPred		0.84		Gain of relative solvent accessibility (P = 0.09)
MVP		0.99
MPC		0.34
ClinPred		0.36	T
GERP RS		3.2
Varity_R		0.67
gMVP		0.65
Mutation Taster		=2/98	disease causing

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: rs1060502583; hg19: chr2-203417534;