rs137852743

Variant names:

• chr2-202467625-T-G
• rs137852743
• NM_001204.7:c.354T>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PS4 PM1_Strong PM5_Supporting PP1 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The BMPR2 c.354T>C variant is a missense variant predicted to cause a cysteine to tryptophan substitution at amino acid position 118 (p.Cys118Trp). The variant is absent from gnomAD exomes v.2.1.1 controls and gnomAD genomes v3.0 (PM2_supporting). More than 4 unrelated pulmonary arterial hypertension probands were identified with this variant (PMID:10973254, PMID:32255665, PMID:33007923, and PMID:31727138) (PS4). In one multigenerational family, the variant segregated with PAH in at least 3 family members (PMID:10973254) (PP1). BMPR2 p.Cys118Trp is located within the conserved extracellular domain and is a Cys residue critical for protein function (PMID:9886286, PMID:12221115, PMID:12045205, PMID:16429395) (PM1_strong). Several well-controlled in vitro functional assays provided variant-specific evidence of protein loss of function (PMID:25688877, PMID:12221115, and PMID:32255665) (PS3). In silico prediction (REVEL =0.9279) is consistent with a pathogenic effect for this variant (PP3). Additionally, another variant in the same codon, BMPR2 (NM_001204.7):c.353G>A:(p.Cys118Tyr), was classified as likely pathogenic (PM5_supporting). In summary, the variant meets the criteria to be classified as pathogenic for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by theClinGen Pulmonary Hypertension VCEP: PS3, PS4, PM1_strong, PM2_supporting, PM5_supporting, PP3, PP1 (VCEP specification version v 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA278075/MONDO:0015924/125

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4 O:1
• Conservation: PhyloP100: 1.11
• Publications: 27 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: Pathogenic. The variant received 16 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.354T>G	p.Cys118Trp	missense	Exon 3 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.354T>G	p.Cys118Trp	missense	Exon 3 of 13	ENSP00000363708.4	Q13873-1
	BMPR2	ENST00000374574.2	TSL:2	c.354T>G	p.Cys118Trp	missense	Exon 3 of 12	ENSP00000363702.2	Q13873-2
	BMPR2	ENST00000479069.1	TSL:3	n.261T>G		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458444 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725766

African (AFR) AF: 0.00 AC: 0 AN: 33392

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108860

Other (OTH) AF: 0.00 AC: 0 AN: 60308

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Pulmonary hypertension, primary, 1 (2)
1	-	-	Primary pulmonary hypertension (1)
1	-	-	Pulmonary arterial hypertension (1)
-	-	-	Pulmonary arterial hypertension;C5679820:Idiopathic and/or familial pulmonary arterial hypertension (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		1.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.96		Loss of disorder (P = 0.0129)
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		1.3
Varity_R		0.99
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs137852743; hg19: chr2-203332348;