rs1060502581

Variant names:

• chr2-202520195-C-T
• rs1060502581
• NM_001204.7:c.961C>T

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_001204.7(BMPR2):​c.961C>T​(p.Arg321*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005908311: Functional in vitro studies have demonstrated reduced BMPR2 protein levels associated with this variant (PMID:23590310), supporting its deleterious effect (PS3_Strong)." and additional evidence is available in ClinVar. Variant results in nonsense mediated mRNA decay. The gene BMPR2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BMPR2 NM_001204.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.14
• Publications: 10 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]

RPL13AP12 (HGNC:35673): (ribosomal protein L13a pseudogene 12)

ACMG classification

Specifications for BMPR2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV005908311: Functional in vitro studies have demonstrated reduced BMPR2 protein levels associated with this variant (PMID: 23590310), supporting its deleterious effect (PS3_Strong).; SCV001156675: "This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. This prediction is supported by in vitro functional analyses, which show reduced transcript and protein levels (Drake 2011, Dunmore 2013)."
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-202520195-C-T is Pathogenic according to our data. Variant chr2-202520195-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 409826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.961C>T	p.Arg321*	stop_gained	Exon 7 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.961C>T	p.Arg321*	stop_gained	Exon 7 of 13	ENSP00000363708.4	Q13873-1
	BMPR2	ENST00000374574.2	TSL:2	c.961C>T	p.Arg321*	stop_gained	Exon 7 of 12	ENSP00000363702.2	Q13873-2
	RPL13AP12	ENST00000435125.1	TSL:6	n.-206C>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456118 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724776

African (AFR) AF: 0.00 AC: 0 AN: 33346

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1106828

Other (OTH) AF: 0.00 AC: 0 AN: 60196

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		2.1
Vest4		0.96
GERP RS		4.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1060502581; hg19: chr2-203384918; COSMIC: COSV65807609; COSMIC: COSV65807609;