2-202464823-G-A

Variant names:

• chr2-202464823-G-A
• rs1085307162
• NM_001204.7:c.91G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1 BS2

The NM_001204.7(BMPR2):​c.91G>A​(p.Glu31Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000822 in 1,460,368 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.13
• Publications: 1 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: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 10 uncertain in NM_001204.7
• BS2: High AC in GnomAdExome4 at 12 AD gene.

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.91G>A	p.Glu31Lys	missense	Exon 2 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.91G>A	p.Glu31Lys	missense	Exon 2 of 13	ENSP00000363708.4
	BMPR2	ENST00000374574.2	TSL:2	c.91G>A	p.Glu31Lys	missense	Exon 2 of 12	ENSP00000363702.2
	BMPR2	ENST00000479069.1	TSL:3	n.-3G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1460368 Hom.: 0 Cov.: 31 AF XY: 0.00000964 AC XY: 7 AN XY: 726252

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 85692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1111422

Other (OTH) AF: 0.0000166 AC: 1 AN: 60338

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Benign	0.059
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	0.55	N
PhyloP100		6.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.50
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.081	T
Polyphen		0.13	B
Vest4		0.73
MutPred		0.33		Gain of ubiquitination at E31 (P = 0.0267)
MVP		0.97
MPC		0.38
ClinPred		0.82	D
GERP RS		5.4
Varity_R		0.44
gMVP		0.93
Mutation Taster		=69/31	polymorphism

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: rs1085307162; hg19: chr2-203329546; COSMIC: COSV101001852;