2-202513675-CTT-CT

Position:

• chr2-202513675-CTT-CT

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BS2 BA1 BP4

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
• Clinical Significance: Benign reviewed by expert panel U:1 B:3
• Conservation: PhyloP100: 1.28

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.419-38del		intron_variant		ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.419-38del		intron_variant			XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.419-38del		intron_variant		1	NM_001204.7	ENSP00000363708	P1
BMPR2	ENST00000374574.2	c.419-38del		intron_variant		2		ENSP00000363702

Frequencies

GnomAD3 genomes AF: 0.125 AC: 19016 AN: 151826 Hom.: 1262 Cov.: 30

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

GnomAD3 exomes AF: 0.126 AC: 31203 AN: 246956 Hom.: 2207 AF XY: 0.126 AC XY: 16832 AN XY: 133982

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 SAS exome AF: 0.129

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.: 16 AF XY: 0.128 AC XY: 84715 AN XY: 663834

Gnomad4 AFR exome AF: 0.108

Gnomad4 AMR exome AF: 0.160

Gnomad4 ASJ exome AF: 0.0630

Gnomad4 EAS exome AF: 0.00224

Gnomad4 SAS exome AF: 0.129

Gnomad4 FIN exome AF: 0.177

Gnomad4 NFE exome AF: 0.131

Gnomad4 OTH exome AF: 0.119

GnomAD4 genome AF: 0.125 AC: 19045 AN: 151942 Hom.: 1266 Cov.: 30 AF XY: 0.127 AC XY: 9412 AN XY: 74272

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.137

Gnomad4 ASJ AF: 0.0692

Gnomad4 EAS AF: 0.00405

Gnomad4 SAS AF: 0.115

Gnomad4 FIN AF: 0.189

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.0974

Alfa AF: 0.123 Hom.: 203

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Pulmonary arterial hypertension associated with congenital heart disease Uncertain:1

Uncertain significance, criteria provided, single submitter

case-control

Wendy Chung Laboratory, Columbia University Medical Center

Jun 27, 2018

- -

Pulmonary arterial hypertension Benign:1

Benign, reviewed by expert panel

curation

Clingen Pulmonary Hypertension Variant Curation Expert Panel, ClinGen

May 03, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 20, 2019

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

Primary pulmonary hypertension Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs10714063; hg19: chr2-203378398;