rs45502895

Variant names:

• chr2-202560052-C-T
• rs45502895
• NM_001204.7:c.*106C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001204.7(BMPR2):​c.*106C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00824 in 1,371,068 control chromosomes in the GnomAD database, including 72 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). The gene BMPR2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0058 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (68 hom.)
• Consequence: BMPR2 NM_001204.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.539
• 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

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 2-202560052-C-T is Benign according to our data. Variant chr2-202560052-C-T is described in ClinVar as Benign. ClinVar VariationId is 333655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00576 (876/152208) while in subpopulation SAS AF = 0.0144 (69/4808). AF 95% confidence interval is 0.0116. There are 4 homozygotes in GnomAd4. There are 435 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 876 AD gene.

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.*106C>T		3_prime_UTR	Exon 13 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.*106C>T		3_prime_UTR	Exon 13 of 13	ENSP00000363708.4	Q13873-1
	BMPR2	ENST00000374574.2	TSL:2	c.*350C>T		3_prime_UTR	Exon 12 of 12	ENSP00000363702.2	Q13873-2

Frequencies

GnomAD3 genomes AF: 0.00577 AC: 877 AN: 152090 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0143

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00911

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.00854 AC: 10415 AN: 1218860 Hom.: 68 Cov.: 17 AF XY: 0.00882 AC XY: 5387 AN XY: 610708

African (AFR) AF: 0.00108 AC: 29 AN: 26828

American (AMR) AF: 0.00246 AC: 84 AN: 34184

Ashkenazi Jewish (ASJ) AF: 0.0102 AC: 235 AN: 23052

East Asian (EAS) AF: 0.0000819 AC: 3 AN: 36644

South Asian (SAS) AF: 0.0144 AC: 1050 AN: 72812

European-Finnish (FIN) AF: 0.00205 AC: 83 AN: 40458

Middle Eastern (MID) AF: 0.0109 AC: 39 AN: 3584

European-Non Finnish (NFE) AF: 0.00917 AC: 8525 AN: 929420

Other (OTH) AF: 0.00707 AC: 367 AN: 51878

GnomAD4 genome AF: 0.00576 AC: 876 AN: 152208 Hom.: 4 Cov.: 32 AF XY: 0.00585 AC XY: 435 AN XY: 74406

African (AFR) AF: 0.00147 AC: 61 AN: 41540

American (AMR) AF: 0.00367 AC: 56 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.0144 AC: 69 AN: 4808

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10580

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00910 AC: 619 AN: 68022

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00625 Hom.: 0

Bravo AF: 0.00535

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Pulmonary hypertension, primary, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.4
DANN	Benign	0.77
PhyloP100		0.54
Mutation Taster		=100/0	polymorphism

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: rs45502895; hg19: chr2-203424775;