2-202513675-CTT-CT

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BA1BP4BS2

This summary comes from the ClinGen Evidence Repository: The BMPR2 c.419-38del is an intronic variant at Intron 3. The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.1814 (2514/13856 alleles) in European (Finnish) population, which is higher than the ClinGen Pulmonary Hypertension Expert Panel threshold (>0.01) for BA1, and therefore meets this stand-alone criterion (BA1). This variant has been observed in 1160 times in homozygous state in healthy individuals (BS2). The computational splicing predictor SpliceAI gives a score of (0.00) for acceptor splice site loss suggesting that the variant has no impact on splicing (BP4). In summary, the variant is classified as benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BA1, BS2, BP4 (VCEP specification version v 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA2061113/MONDO:0015924/125

Frequency

Genomes: 𝑓 0.13 ( 1266 hom., cov: 30)

Exomes 𝑓: 0.13 ( 11456 hom. )

Consequence

BMPR2
NM_001204.7 intron

Scores

Not classified

Clinical Significance

Benign reviewed by expert panel U:1B:3

Conservation

PhyloP100: 1.28

Publications

5 publications found

Variant links:

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

BMPR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

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

BS2

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

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7 link	c.419-38delT		intron_variant	Intron 3 of 12	ENST00000374580.10	NP_001195.2	Q13873-1
BMPR2	XM_011511687.2 link	c.419-38delT		intron_variant	Intron 3 of 12		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10 link	c.419-43delT		intron_variant	Intron 3 of 12	1	NM_001204.7	ENSP00000363708.4		Q13873-1
BMPR2	ENST00000374574.2 link	c.419-43delT		intron_variant	Intron 3 of 11	2		ENSP00000363702.2		Q13873-2

Frequencies

GnomAD3 genomes

AF:

0.125

AC:

19016

AN:

151826

Hom.:

1262

Cov.:

show subpopulations

Gnomad AFR

AF:

0.112

Gnomad AMI

AF:

0.0768

Gnomad AMR

AF:

0.137

Gnomad ASJ

AF:

0.0692

Gnomad EAS

AF:

0.00385

Gnomad SAS

AF:

0.114

Gnomad FIN

AF:

0.189

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.135

Gnomad OTH

AF:

0.0985

GnomAD2 exomes

AF:

0.126

AC:

31203

AN:

246956

AF XY:

0.126

show subpopulations

Gnomad AFR exome

AF:

0.109

Gnomad AMR exome

AF:

0.166

Gnomad ASJ exome

AF:

0.0641

Gnomad EAS exome

AF:

0.00335

Gnomad FIN exome

AF:

0.178

Gnomad NFE exome

AF:

0.133

Gnomad OTH exome

AF:

0.108

GnomAD4 exome

AF:

0.128

AC:

168474

AN:

1318366

Hom.:

11456

Cov.:

AF XY:

0.128

AC XY:

84715

AN XY:

663834

show subpopulations

African (AFR)

AF:

0.108

AC:

3290

AN:

30404

American (AMR)

AF:

0.160

AC:

7122

AN:

44396

Ashkenazi Jewish (ASJ)

AF:

0.0630

AC:

1592

AN:

25266

East Asian (EAS)

AF:

0.00224

AC:

AN:

38772

South Asian (SAS)

AF:

0.129

AC:

10715

AN:

83136

European-Finnish (FIN)

AF:

0.177

AC:

9224

AN:

52100

Middle Eastern (MID)

AF:

0.0911

AC:

413

AN:

4532

European-Non Finnish (NFE)

AF:

0.131

AC:

129413

AN:

984296

Other (OTH)

AF:

0.119

AC:

6618

AN:

55464

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

6908

13816

20723

27631

34539

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4394

8788

13182

17576

21970

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.125

AC:

19045

AN:

151942

Hom.:

1266

Cov.:

AF XY:

0.127

AC XY:

9412

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.113

AC:

4670

AN:

41448

American (AMR)

AF:

0.137

AC:

2085

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.0692

AC:

240

AN:

3470

East Asian (EAS)

AF:

0.00405

AC:

AN:

5180

South Asian (SAS)

AF:

0.115

AC:

552

AN:

4812

European-Finnish (FIN)

AF:

0.189

AC:

1989

AN:

10518

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.135

AC:

9194

AN:

67942

Other (OTH)

AF:

0.0974

AC:

205

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

863

1726

2588

3451

4314

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

210

420

630

840

1050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.123

Hom.:

203

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Pulmonary arterial hypertension associated with congenital heart disease

Uncertain:1

Jun 27, 2018

Wendy Chung Laboratory, Boston Children's Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:case-control

- -

Pulmonary arterial hypertension

Benign:1

May 03, 2024

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The BMPR2 c.419-38del is an intronic variant at Intron 3. The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.1814 (2514/13856 alleles) in European (Finnish) population, which is higher than the ClinGen Pulmonary Hypertension Expert Panel threshold (>0.01) for BA1, and therefore meets this stand-alone criterion (BA1). This variant has been observed in 1160 times in homozygous state in healthy individuals (BS2). The computational splicing predictor SpliceAI gives a score of (0.00) for acceptor splice site loss suggesting that the variant has no impact on splicing (BP4). In summary, the variant is classified as benign for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BA1, BS2, BP4 (VCEP specification version v 1.1, 1/18/2024). -

not provided

Benign:1

Sep 20, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 30029678) -

Primary pulmonary hypertension

Benign:1

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over