NM_001204.7:c.1277-9A>C

Variant names:

• chr2-202542302-A-C
• rs1085307331
• NM_001204.7:c.1277-9A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. BP4 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The BMPR2 c.1277-9A>C variant is a non-canonical splice site (-9) variant located in intron 9. The variant is absent from gnomAD v.2.1.1 and v4.1.0 (PM2_supporting) and was reported in a single proband with PAH (PMID:19555857). In silico prediction (SpliceAI) indicates no impact on splicing (BP4). No familial segregation data were available, and no functional analysis has been reported for this variant. In summary, the variant meets the criteria to be classified as a variant of uncertain significance for pulmonary arterial hypertension based on the ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: PM2_supporting, BP4 (VCEP specification version v1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA645293837/MONDO:0015924/125

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMPR2 NM_001204.7 intron
• Scores: Splicing: ADA: 0.008567
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: 2.31
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: 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.1277-9A>C		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.1277-9A>C		intron	N/A	ENSP00000363708.4	Q13873-1
	BMPR2	ENST00000374574.2	TSL:2	c.1277-9A>C		intron	N/A	ENSP00000363702.2	Q13873-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Pulmonary arterial hypertension (1)
1	-	-	Pulmonary hypertension, primary, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.93
PhyloP100		2.3
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0086
dbscSNV1_RF	Benign	0.27
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: rs1085307331; hg19: chr2-203407025;