rs115604088

Variant names:

• chr2-202376806-G-A
• rs115604088
• NM_001204.7:c.-669G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-202376806-G-A
• chr2-202376806-G-C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The BMPR2 c.-669G>A variant is a 5’UTR variant with contradictory evidence for a functional promoter effect (PMID:19223935 and PMID:30336198). Both reports included luciferase assays comparing transcriptional activity of cells expressing wild-type or variant promoter constructs. PMID:19223935 reported a negative effect on BMPR2 expression but the assay used a short 300 bp promoter fragment and no known pathogenic or benign variant controls. PMID:30336198 reported no effect on BMPR2 expression using longer 1520 bp promoter fragments and included nine different PAH associated variants. Based on the latter report, PS3 was not applied. PMID:26387786 reported three PAH probands with the c.-669G>A variant. However, the variant has also been identified in numerous individuals from control populations. In gnomAD v2.1.1 controls (11/2022), the Estonian population had an AF of 2.65% (105/3956 alleles, including 2 homozygotes) which is higher than the ClinGen Pulmonary Hypertension VCEP threshold of >1% for BA1, and therefore meets this stand-alone criterion (BA1). In summary, the variant meets the criteria to be classified as benign for pulmonary arterial hypertension based on ACMG/AMP criteria applied, as specified by the ClinGen Pulmonary Hypertension VCEP: BA1 (VCEP specification version 1.1, 1/18/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10613567/MONDO:0015924/125

• Frequency:
  • Genomes: 𝑓 0.0061 (11 hom., cov: 31)
  • Exomes 𝑓: 0.0082 (13 hom.)
• Consequence: BMPR2 NM_001204.7 5_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:8
• Conservation: PhyloP100: 0.918
• Publications: 5 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

ENSG00000273456 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: 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.-669G>A		5_prime_UTR	Exon 1 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.-669G>A		5_prime_UTR	Exon 1 of 13	ENSP00000363708.4
	ENSG00000273456	ENST00000724884.1		n.139C>T		non_coding_transcript_exon	Exon 1 of 2
	ENSG00000273456	ENST00000724885.1		n.-68C>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 922 AN: 151324 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.00119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00199

Gnomad SAS AF: 0.00233

Gnomad FIN AF: 0.0185

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00914

Gnomad OTH AF: 0.00291

GnomAD4 exome AF: 0.00818 AC: 2044 AN: 249938 Hom.: 13 AF XY: 0.00810 AC XY: 1030 AN XY: 127140

African (AFR) AF: 0.00125 AC: 9 AN: 7176

American (AMR) AF: 0.00103 AC: 8 AN: 7756

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 17 AN: 9258

East Asian (EAS) AF: 0.00200 AC: 46 AN: 22970

South Asian (SAS) AF: 0.00210 AC: 6 AN: 2854

European-Finnish (FIN) AF: 0.0214 AC: 445 AN: 20832

Middle Eastern (MID) AF: 0.00383 AC: 5 AN: 1304

European-Non Finnish (NFE) AF: 0.00871 AC: 1404 AN: 161246

Other (OTH) AF: 0.00629 AC: 104 AN: 16542

GnomAD4 genome AF: 0.00608 AC: 921 AN: 151442 Hom.: 11 Cov.: 31 AF XY: 0.00647 AC XY: 478 AN XY: 73926

African (AFR) AF: 0.00118 AC: 49 AN: 41358

American (AMR) AF: 0.00171 AC: 26 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

East Asian (EAS) AF: 0.00199 AC: 10 AN: 5022

South Asian (SAS) AF: 0.00212 AC: 10 AN: 4722

European-Finnish (FIN) AF: 0.0185 AC: 195 AN: 10552

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

European-Non Finnish (NFE) AF: 0.00914 AC: 620 AN: 67846

Other (OTH) AF: 0.00288 AC: 6 AN: 2084

Alfa AF: 0.00835 Hom.: 17

Bravo AF: 0.00432

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.9
DANN	Benign	0.74
PhyloP100		0.92
PromoterAI		-0.049	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs115604088; hg19: chr2-203241529;