chr2-202376548-A-G

Variant names:

• chr2-202376548-A-G
• rs530181389
• NM_001204.7:c.-927A>G

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.-927A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0059 in 117,236 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency: Genomes: 𝑓 0.0059 (2 hom., cov: 24)
• Consequence: BMPR2 NM_001204.7 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.93
• Publications: 0 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

ENSG00000273456 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-202376548-A-G is Benign according to our data. Variant chr2-202376548-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 333622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0059 (692/117236) while in subpopulation AFR AF = 0.0166 (547/33018). AF 95% confidence interval is 0.0154. There are 2 homozygotes in GnomAd4. There are 335 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High AC in GnomAd4 at 692 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.-927A>G		5_prime_UTR	Exon 1 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.-927A>G		5_prime_UTR	Exon 1 of 13	ENSP00000363708.4	Q13873-1
	ENSG00000273456	ENST00000724884.1		n.154+243T>C		intron	N/A
	ENSG00000273456	ENST00000724885.1		n.106+85T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00589 AC: 690 AN: 117158 Hom.: 2 Cov.: 24

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.000345

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000247

Gnomad MID AF: 0.0177

Gnomad NFE AF: 0.00142

Gnomad OTH AF: 0.00741

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00590 AC: 692 AN: 117236 Hom.: 2 Cov.: 24 AF XY: 0.00594 AC XY: 335 AN XY: 56434

African (AFR) AF: 0.0166 AC: 547 AN: 33018

American (AMR) AF: 0.00467 AC: 51 AN: 10922

Ashkenazi Jewish (ASJ) AF: 0.000345 AC: 1 AN: 2902

East Asian (EAS) AF: 0.00 AC: 0 AN: 4274

South Asian (SAS) AF: 0.00 AC: 0 AN: 2794

European-Finnish (FIN) AF: 0.000247 AC: 2 AN: 8084

Middle Eastern (MID) AF: 0.0192 AC: 5 AN: 260

European-Non Finnish (NFE) AF: 0.00142 AC: 75 AN: 52702

Other (OTH) AF: 0.00729 AC: 11 AN: 1508

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	-0.56
CADD	Benign	9.2
DANN	Benign	0.63
PhyloP100		-1.9
PromoterAI		-0.0094	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs530181389; hg19: chr2-203241271;