chr2-202467591-C-T

Variant names:

• chr2-202467591-C-T
• rs1085307208
• NM_001204.7:c.320C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001204.7(BMPR2):​c.320C>T​(p.Ser107Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,438,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S107P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: BMPR2 NM_001204.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.36
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_001204.7
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19124678).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.320C>T	p.Ser107Leu	missense_variant	Exon 3 of 13	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.320C>T	p.Ser107Leu	missense_variant	Exon 3 of 13		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.320C>T	p.Ser107Leu	missense_variant	Exon 3 of 13	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.320C>T	p.Ser107Leu	missense_variant	Exon 3 of 12	2		ENSP00000363702.2
BMPR2	ENST00000479069.1	n.227C>T		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1438496 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 717154

African (AFR) AF: 0.00 AC: 0 AN: 32890

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25990

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39566

South Asian (SAS) AF: 0.00 AC: 0 AN: 85758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090786

Other (OTH) AF: 0.00 AC: 0 AN: 59686

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.032
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	-0.13	N;N;.
PhyloP100		1.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.9	N;N;.
REVEL	Uncertain	0.36
Sift	Benign	0.31	T;T;.
Sift4G	Benign	0.30	T;T;.
Polyphen		0.0	B;.;.
Vest4		0.15
MutPred		0.46		Loss of glycosylation at S107 (P = 0.034);Loss of glycosylation at S107 (P = 0.034);.;
MVP		0.69
MPC		0.29
ClinPred		0.68	D
GERP RS		5.4
Varity_R		0.26
gMVP		0.32
Mutation Taster		=53/47	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1085307208; hg19: chr2-203332314;