rs140683387

Variant names:

• chr2-202467547-A-C
• rs140683387
• NM_001204.7:c.276A>C

Your query was ambiguous. Multiple possible variants found:

• chr2-202467547-A-C
• chr2-202467547-A-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1 BS1

This summary comes from the ClinGen Evidence Repository: The BMPR2 c.276A>C variant is a missense variant predicted to cause substitution of glutamine to histidine at amino acid position 92 (p.(Gln92His)). The highest population minor allele frequency in gnomAD v2.1.1 (controls) is 0.001589 in the East Asian population (Korean) (BS1 met but not PM2 or BA1). Computational predictor REVEL score is 0.57, which is in between the PH-VCEP specified threshold of ≤0.25 and ≥0.75, so neither PP3 nor BP4 are met. This variant is located in the extracellular domain, critical for ligand binding (PM1 met), but does not affect a known critical or non-critical amino acid (no up- or downward adjustment for PM1). BS2 was not met due to absence of homozygous individuals (gnomAD v.2.1.1 controls). PS4 was not applied as PM2 was not met. PP1, PS2, PM6 were not met due to the absence of co-segregation data. PS3 and BS3 were not met due to the lack of experimental evidence. Although other variants in the same amino acid been reported, for pulmonary arterial hypertension, the variants were not deemed pathogenic or likely pathogenic by the PH-VCEP (PS1, PM5 not met). 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, PM1 (VCEP specification version 1.1.0, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA2061080/MONDO:0015924/125

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Likely benign reviewed by expert panel U:5 B:2
• Conservation: PhyloP100: 0.115
• Publications: 9 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 -2 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR2	NM_001204.7	MANE Select	c.276A>C	p.Gln92His	missense	Exon 3 of 13	NP_001195.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMPR2	ENST00000374580.10	TSL:1 MANE Select	c.276A>C	p.Gln92His	missense	Exon 3 of 13	ENSP00000363708.4
	BMPR2	ENST00000374574.2	TSL:2	c.276A>C	p.Gln92His	missense	Exon 3 of 12	ENSP00000363702.2
	BMPR2	ENST00000479069.1	TSL:3	n.183A>C		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251434 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000828 AC: 117 AN: 1413464 Hom.: 0 Cov.: 31 AF XY: 0.0000822 AC XY: 58 AN XY: 705688

African (AFR) AF: 0.00 AC: 0 AN: 32328

American (AMR) AF: 0.0000224 AC: 1 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25856

East Asian (EAS) AF: 0.00294 AC: 116 AN: 39454

South Asian (SAS) AF: 0.00 AC: 0 AN: 85256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5680

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1068002

Other (OTH) AF: 0.00 AC: 0 AN: 58852

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74418

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

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000225 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	2	-	Pulmonary hypertension, primary, 1 (2)
-	-	1	Primary pulmonary hypertension (1)
-	-	1	Pulmonary arterial hypertension (1)
-	1	-	Pulmonary venoocclusive disease 1;C4552070:Pulmonary hypertension, primary, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.75	D
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.052	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.12
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.57
Sift	Benign	0.31	T
Sift4G	Benign	0.26	T
Polyphen		0.0010	B
Vest4		0.38
MutPred		0.62		Loss of helix (P = 0.079)
MVP		1.0
MPC		0.32
ClinPred		0.33	T
GERP RS		-0.45
Varity_R		0.22
gMVP		0.61
Mutation Taster		=5/95	disease causing

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: rs140683387; hg19: chr2-203332270;