rs1085307325

Variant names:

• chr2-202532715-G-A
• rs1085307325
• NM_001204.7:c.1259G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS4_Moderate PM1 PM5 PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: BMPR2 c.1259G>A is a missense variant predicted to cause substitution of cysteine to tyrosine at amino acid position 420 (p.Cys420Tyr). The variant is absent from gnomAD v2.1.1 and v4.1 (PM2_supporting). A REVEL score of 0.924 meets PP3_supporting (>0.75). This variant resides within the conserved catalytic kinase domain but does not affect a known critical residue (PM1_moderate). The variant has been reported in four unrelated PAH probands (PMID:15146475, 16429395, 21737554) with additional citations referring back to the same individuals (PMID:21801371, 32634488, 30578397) (PS4_moderate). A different missense variant at the same amino acid residue, p.Cys420Arg (PMID:11115378, 21801371) was previously classified by the PH VCEP as pathogenic (PM5_moderate). In summary, this variant meets the criteria to be classified as a likely pathogenic variant for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PS4_moderate, PM1_moderate, PM5_moderate, PM2_supporting, PP3_supporting (VCEP specification version 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA350341979/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 31)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 9.64
• Publications: 5 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_pathogenic. The variant received 8 ACMG points.

• 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.
• 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.1259G>A	p.Cys420Tyr	missense	Exon 9 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.1259G>A	p.Cys420Tyr	missense	Exon 9 of 13	ENSP00000363708.4	Q13873-1
	BMPR2	ENST00000374574.2	TSL:2	c.1259G>A	p.Cys420Tyr	missense	Exon 9 of 12	ENSP00000363702.2	Q13873-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Primary pulmonary hypertension (1)
1	-	-	Pulmonary arterial hypertension (1)
1	-	-	Pulmonary hypertension, primary, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.87		Loss of catalytic residue at M418 (P = 1e-04)
MVP		0.99
MPC		1.4
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.95
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1085307325; hg19: chr2-203397438; COSMIC: COSV101001450;