rs1061157

Variant names:

• chr2-202556476-G-A
• rs1061157
• NM_001204.7:c.2811G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001204.7(BMPR2):​c.2811G>A​(p.Arg937Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,613,998 control chromosomes in the GnomAD database, including 12,623 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (883 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11740 hom.)
• Consequence: BMPR2 NM_001204.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.44
• Publications: 28 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 2-202556476-G-A is Benign according to our data. Variant chr2-202556476-G-A is described in ClinVar as Benign. ClinVar VariationId is 136529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

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.2811G>A	p.Arg937Arg	synonymous	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.2811G>A	p.Arg937Arg	synonymous	Exon 12 of 13	ENSP00000363708.4	Q13873-1
	BMPR2	ENST00000374574.2	TSL:2	c.1587-3220G>A		intron	N/A	ENSP00000363702.2	Q13873-2

Frequencies

GnomAD3 genomes AF: 0.0934 AC: 14207 AN: 152100 Hom.: 883 Cov.: 32

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.0870

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0690

Gnomad EAS AF: 0.0966

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.120

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.119 AC: 29883 AN: 251166 AF XY: 0.127

Gnomad AFR exome AF: 0.0203

Gnomad AMR exome AF: 0.0829

Gnomad ASJ exome AF: 0.0751

Gnomad EAS exome AF: 0.105

Gnomad FIN exome AF: 0.122

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.120 AC: 175695 AN: 1461780 Hom.: 11740 Cov.: 33 AF XY: 0.124 AC XY: 90147 AN XY: 727184

African (AFR) AF: 0.0176 AC: 588 AN: 33480

American (AMR) AF: 0.0842 AC: 3767 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0762 AC: 1991 AN: 26136

East Asian (EAS) AF: 0.0754 AC: 2994 AN: 39700

South Asian (SAS) AF: 0.234 AC: 20197 AN: 86254

European-Finnish (FIN) AF: 0.123 AC: 6582 AN: 53338

Middle Eastern (MID) AF: 0.116 AC: 670 AN: 5768

European-Non Finnish (NFE) AF: 0.118 AC: 131561 AN: 1111986

Other (OTH) AF: 0.122 AC: 7345 AN: 60394

GnomAD4 genome AF: 0.0933 AC: 14196 AN: 152218 Hom.: 883 Cov.: 32 AF XY: 0.0959 AC XY: 7138 AN XY: 74420

African (AFR) AF: 0.0211 AC: 876 AN: 41568

American (AMR) AF: 0.108 AC: 1658 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0690 AC: 239 AN: 3462

East Asian (EAS) AF: 0.0964 AC: 500 AN: 5186

South Asian (SAS) AF: 0.243 AC: 1169 AN: 4820

European-Finnish (FIN) AF: 0.116 AC: 1226 AN: 10584

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.120 AC: 8162 AN: 68004

Other (OTH) AF: 0.115 AC: 242 AN: 2110

Alfa AF: 0.106 Hom.: 1515

Bravo AF: 0.0852

Asia WGS AF: 0.186 AC: 644 AN: 3478

EpiCase AF: 0.116

EpiControl AF: 0.115

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Primary pulmonary hypertension (1)
-	-	1	Pulmonary hypertension, primary, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.8
DANN	Benign	0.55
PhyloP100		1.4
Mutation Taster		=99/1	polymorphism (auto)

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: rs1061157; hg19: chr2-203421199; COSMIC: COSV65809637;