rs148099152

Variant names:

• chr2-202559777-G-A
• rs148099152
• NM_001204.7:c.2948G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

This summary comes from the ClinGen Evidence Repository: The NM_001204.7(BMPR2):c.2948G>A variant is a missense variant predicted to cause substitution of arginine to glutamine at amino acid position 983 (p.Arg983Gln). The highest population minor allele frequency in gnomAD v2.1.1 controls is 0.0034 (8/2358) in the Ashkenazi Jew population, which is higher than the ClinGen PH VCEP threshold (>0.1%) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.4, which is neither above nor below the thresholds predicting a damaging or benign impact on BMPR2 function. 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: BS1. (VCEP specifications version 1.1, 1/18/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA2061617/MONDO:0015924/125

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:3
• Conservation: PhyloP100: 6.52
• Publications: 2 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

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

• BS1: 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.2948G>A	p.Arg983Gln	missense	Exon 13 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.2948G>A	p.Arg983Gln	missense	Exon 13 of 13	ENSP00000363708.4	Q13873-1
	BMPR2	ENST00000374574.2	TSL:2	c.*75G>A		3_prime_UTR	Exon 12 of 12	ENSP00000363702.2	Q13873-2

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000263 AC: 66 AN: 251368 AF XY: 0.000243

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00456

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000191 AC: 279 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.000187 AC XY: 136 AN XY: 727238

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

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00589 AC: 154 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000863 AC: 96 AN: 1112000

Other (OTH) AF: 0.000331 AC: 20 AN: 60394

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74430

African (AFR) AF: 0.00 AC: 0 AN: 41538

American (AMR) AF: 0.000458 AC: 7 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68032

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000460 Hom.: 0

Bravo AF: 0.000276

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000206 AC: 25

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	Pulmonary hypertension, primary, 1 (2)
-	1	-	Mitral valve prolapse;C0085615:Complete right bundle branch block;C0162770:Right ventricular hypertrophy;C0344893:Right ventricular dilatation;C0428851:Pulmonary artery dilatation;C1867421:Elevated right atrial pressure;C1867423:Increased pulmonary vascular resistance;C2973725:Pulmonary arterial hypertension (1)
-	1	-	not provided (1)
-	-	1	Primary pulmonary hypertension (1)
-	-	1	Pulmonary arterial hypertension (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.029	T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	2.0	M
PhyloP100		6.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.60	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.026	D
Polyphen		0.97	D
Vest4		0.47
MVP		0.82
MPC		0.39
ClinPred		0.064	T
GERP RS		5.7
Varity_R		0.26
gMVP		0.23
Mutation Taster		=73/27	polymorphism

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: rs148099152; hg19: chr2-203424500; COSMIC: COSV65811601;