rs12468226

Variant names:

• chr2-202472278-A-G
• rs12468226
• NM_001204.7:c.418+4589A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001204.7(BMPR2):​c.418+4589A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0987 in 152,252 control chromosomes in the GnomAD database, including 991 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.099 (991 hom., cov: 33)
• Consequence: BMPR2 NM_001204.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.144
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.418+4589A>G		intron_variant	Intron 3 of 12	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.418+4589A>G		intron_variant	Intron 3 of 12		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.418+4589A>G		intron_variant	Intron 3 of 12	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.418+4589A>G		intron_variant	Intron 3 of 11	2		ENSP00000363702.2
BMPR2	ENST00000479069.1	n.326-2430A>G		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0988 AC: 15037 AN: 152134 Hom.: 992 Cov.: 33

Gnomad AFR AF: 0.0228

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.0691

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.124

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

GnomAD4 genome AF: 0.0987 AC: 15026 AN: 152252 Hom.: 991 Cov.: 33 AF XY: 0.102 AC XY: 7558 AN XY: 74438

African (AFR) AF: 0.0228 AC: 946 AN: 41580

American (AMR) AF: 0.138 AC: 2107 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0691 AC: 240 AN: 3472

East Asian (EAS) AF: 0.117 AC: 605 AN: 5180

South Asian (SAS) AF: 0.247 AC: 1192 AN: 4826

European-Finnish (FIN) AF: 0.118 AC: 1249 AN: 10602

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8301 AN: 68010

Other (OTH) AF: 0.124 AC: 262 AN: 2114

Alfa AF: 0.0849 Hom.: 305

Bravo AF: 0.0947

Asia WGS AF: 0.203 AC: 705 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.9
DANN	Benign	0.42
PhyloP100		0.14
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: rs12468226; hg19: chr2-203337001;