rs397514496

Variant names:

• chr2-202514962-A-T
• rs397514496
• NM_001204.7:c.604A>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001204.7(BMPR2):​c.604A>T​(p.Asn202Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: 8.69
• Publications: 4 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877
• PP5: Variant 2-202514962-A-T is Pathogenic according to our data. Variant chr2-202514962-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 39422.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.604A>T	p.Asn202Tyr	missense_variant	Exon 5 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.604A>T	p.Asn202Tyr	missense_variant	Exon 5 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.604A>T	p.Asn202Tyr	missense_variant	Exon 5 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.604A>T	p.Asn202Tyr	missense_variant	Exon 5 of 12	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Pulmonary venoocclusive disease 1 Pathogenic:1

Jul 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Familial pulmonary capillary hemangiomatosis Uncertain:1

May 12, 2023

UF D’onco_angiogenetique Et Genomique Des Tumeurs Solides, APHP Sorbonne Universite Hopital Pitie Salpetriere

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant was identified in a patient with PVOD (same patient as the one described in PMID: 18626305) for whom a biallelic pathogenic variant was identified in the EIF2AK4 gene (PMID: 24292273. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.8	L;L;.
PhyloP100		8.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.4	D;D;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.018	D;D;.
Polyphen		0.40	B;.;.
Vest4		0.76
MutPred		0.75		Gain of phosphorylation at N202 (P = 0.0401);Gain of phosphorylation at N202 (P = 0.0401);.;
MVP		0.96
MPC		0.48
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.79
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs397514496; hg19: chr2-203379685;