NM_001204.7:c.2656C>T

Variant names:

• chr2-202556321-C-T
• rs148770894
• NM_001204.7:c.2656C>T

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 BMPR2 c.2656C>T variant is a missense variant predicted to cause an arginine to cysteine substitution at amino acid position 886. The highest population minor allele frequency in gnomAD v.2.1.1 controls is 0.1130% (11/9738 alleles) in the African/African American population. The population evidence available meets the threshold for BS1 (≥0.1%), but not for BA1 (>5%) or PM2 (<0.01%) as defined by the ClinGen Pulmonary Hypertension VCEP (PH-VCEP). Computational evidence for pathogenicity as evaluated by REVEL generated a score of 0.485 indicating that neither BP4 or PP3 were met since the threshold specified by the PH-VCEP is <0.25 and >0.75, respectively. The amino acid substitution occurs in the c-terminal domain, which is not a well-established functional domain, so PM1 was not met. Criteria not evaluated included PP1, PM6, and PS2 due to the absence of segregation data. BS3 and PS3 were not evaluated due to the lack of functional data for this variant. In summary, the variant meets the criteria to be classified as likely benign (LB) for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BS1 (VCEP specification version 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA2061559/MONDO:0015924/125

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:2
• Conservation: PhyloP100: 2.90
• Publications: 0 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.2656C>T	p.Arg886Cys	missense	Exon 12 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.2656C>T	p.Arg886Cys	missense	Exon 12 of 13	ENSP00000363708.4	Q13873-1
	BMPR2	ENST00000374574.2	TSL:2	c.1587-3375C>T		intron	N/A	ENSP00000363702.2	Q13873-2

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000103 AC: 26 AN: 251458 AF XY: 0.0000515

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000376 AC: 55 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 727234

African (AFR) AF: 0.000956 AC: 32 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1112010

Other (OTH) AF: 0.0000828 AC: 5 AN: 60394

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74470

African (AFR) AF: 0.00130 AC: 54 AN: 41568

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.000397

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	1	Primary pulmonary hypertension (1)
-	-	1	Pulmonary arterial hypertension (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.23	T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.9	L
PhyloP100		2.9
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.48
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.64
MVP		0.93
MPC		1.2
ClinPred		0.095	T
GERP RS		6.2
Varity_R		0.31
gMVP		0.25
Mutation Taster		=43/57	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: rs148770894; hg19: chr2-203421044;