2-202513893-C-T

Variant names:

• chr2-202513893-C-T
• rs7575056
• NM_001204.7:c.529+64C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001204.7(BMPR2):​c.529+64C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,290,226 control chromosomes in the GnomAD database, including 11,421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1185 hom., cov: 32)
  • Exomes 𝑓: 0.13 (10236 hom.)
• Consequence: BMPR2 NM_001204.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.50
• Publications: 3 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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-202513893-C-T is Benign according to our data. Variant chr2-202513893-C-T is described in ClinVar as [Benign]. Clinvar id is 1281801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.529+64C>T		intron_variant	Intron 4 of 12	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.529+64C>T		intron_variant	Intron 4 of 12		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.529+64C>T		intron_variant	Intron 4 of 12	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.529+64C>T		intron_variant	Intron 4 of 11	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18050 AN: 151674 Hom.: 1182 Cov.: 32

Gnomad AFR AF: 0.0901

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.0693

Gnomad EAS AF: 0.00387

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.0903

GnomAD4 exome AF: 0.129 AC: 146636 AN: 1138432 Hom.: 10236 AF XY: 0.129 AC XY: 74512 AN XY: 579616

African (AFR) AF: 0.0865 AC: 2290 AN: 26464

American (AMR) AF: 0.156 AC: 6313 AN: 40472

Ashkenazi Jewish (ASJ) AF: 0.0632 AC: 1492 AN: 23592

East Asian (EAS) AF: 0.00222 AC: 84 AN: 37874

South Asian (SAS) AF: 0.130 AC: 9886 AN: 76306

European-Finnish (FIN) AF: 0.179 AC: 9098 AN: 50822

Middle Eastern (MID) AF: 0.0897 AC: 350 AN: 3904

European-Non Finnish (NFE) AF: 0.134 AC: 111174 AN: 829448

Other (OTH) AF: 0.120 AC: 5949 AN: 49550

GnomAD4 genome AF: 0.119 AC: 18067 AN: 151794 Hom.: 1185 Cov.: 32 AF XY: 0.120 AC XY: 8937 AN XY: 74168

African (AFR) AF: 0.0901 AC: 3731 AN: 41392

American (AMR) AF: 0.136 AC: 2073 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.0693 AC: 240 AN: 3462

East Asian (EAS) AF: 0.00407 AC: 21 AN: 5156

South Asian (SAS) AF: 0.115 AC: 554 AN: 4812

European-Finnish (FIN) AF: 0.188 AC: 1974 AN: 10482

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9197 AN: 67946

Other (OTH) AF: 0.0894 AC: 188 AN: 2104

Alfa AF: 0.126 Hom.: 195

Bravo AF: 0.112

Asia WGS AF: 0.0450 AC: 157 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.78
DANN	Benign	0.77
PhyloP100		-1.5
Mutation Taster		=100/0	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: rs7575056; hg19: chr2-203378616;