2-202376511-AGGCGGCGGCGGCGGCGGCGGCGGCGGC-AGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGCGGC

Variant names:

• chr2-202376511-A-AGGCGGCGGCGGCGGCGGC
• rs375624016
• NM_001204.7:c.-945_-928dupGGCGGCGGCGGCGGCGGC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001204.7(BMPR2):​c.-945_-928dupGGCGGCGGCGGCGGCGGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.00099 (1 hom., cov: 16)
• Consequence: BMPR2 NM_001204.7 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.67
• 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

ENSG00000273456 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000993 (125/125852) while in subpopulation NFE AF = 0.000866 (51/58918). AF 95% confidence interval is 0.000676. There are 1 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 16. This position passed quality control check.
• BS2: High AC in GnomAd4 at 125 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.-945_-928dupGGCGGCGGCGGCGGCGGC		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.-945_-928dupGGCGGCGGCGGCGGCGGC		5_prime_UTR	Exon 1 of 13	ENSP00000363708.4	Q13873-1
	ENSG00000273456	ENST00000724884.1		n.154+262_154+279dupGCCGCCGCCGCCGCCGCC		intron	N/A
	ENSG00000273456	ENST00000724885.1		n.106+104_106+121dupGCCGCCGCCGCCGCCGCC		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000994 AC: 125 AN: 125748 Hom.: 1 Cov.: 16

Gnomad AFR AF: 0.000147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000424

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000239

Gnomad SAS AF: 0.000679

Gnomad FIN AF: 0.00704

Gnomad MID AF: 0.00368

Gnomad NFE AF: 0.000865

Gnomad OTH AF: 0.00129

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

GnomAD4 genome AF: 0.000993 AC: 125 AN: 125852 Hom.: 1 Cov.: 16 AF XY: 0.00113 AC XY: 68 AN XY: 60236

African (AFR) AF: 0.000147 AC: 5 AN: 34012

American (AMR) AF: 0.000423 AC: 5 AN: 11822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3186

East Asian (EAS) AF: 0.000240 AC: 1 AN: 4174

South Asian (SAS) AF: 0.000680 AC: 2 AN: 2942

European-Finnish (FIN) AF: 0.00704 AC: 58 AN: 8238

Middle Eastern (MID) AF: 0.00385 AC: 1 AN: 260

European-Non Finnish (NFE) AF: 0.000866 AC: 51 AN: 58918

Other (OTH) AF: 0.00127 AC: 2 AN: 1574

Alfa AF: 0.00 Hom.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7

Splicing

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

Other links and lift over

dbSNP: rs375624016; hg19: chr2-203241234;