rs45502895

Positions:

• chr2-202560052-C-T

Variant summary

Our verdict is Benign. Variant got -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 (★★).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 876 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.*106C>T		3_prime_UTR_variant	13/13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.*106C>T		3_prime_UTR_variant	13/13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.*106C>T		3_prime_UTR_variant	13/13	1	NM_001204.7	ENSP00000363708	P1
BMPR2	ENST00000374574.2	c.*350C>T		3_prime_UTR_variant	12/12	2		ENSP00000363702

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

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.0102

Gnomad4 EAS exome AF: 0.0000819

Gnomad4 SAS exome AF: 0.0144

Gnomad4 FIN exome AF: 0.00205

Gnomad4 NFE exome AF: 0.00917

Gnomad4 OTH exome AF: 0.00707

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

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00367

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0144

Gnomad4 FIN AF: 0.00170

Gnomad4 NFE AF: 0.00910

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00625 Hom.: 0

Bravo AF: 0.00535

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Pulmonary hypertension, primary, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.4
DANN	Benign	0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs45502895; hg19: chr2-203424775;