2-202513675-CTT-CT

Variant names:

• chr2-202513675-CT-C
• rs10714063
• NM_001204.7:c.419-38delT

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BA1 BP4 BS2

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
• 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

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.

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.419-38delT		intron	N/A	NP_001195.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR2	ENST00000374580.10	TSL:1 MANE Select	c.419-43delT		intron	N/A	ENSP00000363708.4	Q13873-1
	BMPR2	ENST00000374574.2	TSL:2	c.419-43delT		intron	N/A	ENSP00000363702.2	Q13873-2

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

GnomAD2 exomes AF: 0.126 AC: 31203 AN: 246956 AF XY: 0.126

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

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: 87 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

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

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: 21 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: 19 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9194 AN: 67942

Other (OTH) AF: 0.0974 AC: 205 AN: 2104

Alfa AF: 0.123 Hom.: 203

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Primary pulmonary hypertension (1)
-	-	1	Pulmonary arterial hypertension (1)
-	1	-	Pulmonary arterial hypertension associated with congenital heart disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10714063; hg19: chr2-203378398;