2-202520065-T-TC

Variant names:

• chr2-202520065-T-TC
• rs11464745
• NM_001204.7:c.853-21dupC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001204.7(BMPR2):​c.853-21dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0366 in 1,484,684 control chromosomes in the GnomAD database, including 614 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (185 hom., cov: 22)
  • Exomes 𝑓: 0.036 (429 hom.)
• Consequence: BMPR2 NM_001204.7 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.06
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 2-202520065-T-TC is Benign according to our data. Variant chr2-202520065-T-TC is described in ClinVar as Likely_benign. ClinVar VariationId is 257625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0741 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMPR2	NM_001204.7	c.853-21dupC		intron_variant	Intron 6 of 12	ENST00000374580.10	NP_001195.2
BMPR2	XM_011511687.2	c.853-21dupC		intron_variant	Intron 6 of 12		XP_011509989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMPR2	ENST00000374580.10	c.853-22_853-21insC		intron_variant	Intron 6 of 12	1	NM_001204.7	ENSP00000363708.4
BMPR2	ENST00000374574.2	c.853-22_853-21insC		intron_variant	Intron 6 of 11	2		ENSP00000363702.2

Frequencies

GnomAD3 genomes AF: 0.0425 AC: 6430 AN: 151402 Hom.: 185 Cov.: 22

Gnomad AFR AF: 0.0505

Gnomad AMI AF: 0.233

Gnomad AMR AF: 0.0405

Gnomad ASJ AF: 0.0764

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0338

Gnomad FIN AF: 0.00813

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0424

Gnomad OTH AF: 0.0466

GnomAD2 exomes AF: 0.0356 AC: 8018 AN: 225004 AF XY: 0.0360

Gnomad AFR exome AF: 0.0469

Gnomad AMR exome AF: 0.0318

Gnomad ASJ exome AF: 0.0713

Gnomad EAS exome AF: 0.000121

Gnomad FIN exome AF: 0.00951

Gnomad NFE exome AF: 0.0429

Gnomad OTH exome AF: 0.0495

GnomAD4 exome AF: 0.0360 AC: 47976 AN: 1333168 Hom.: 429 Cov.: 20 AF XY: 0.0363 AC XY: 24328 AN XY: 669596

African (AFR) AF: 0.0483 AC: 1476 AN: 30564

American (AMR) AF: 0.0312 AC: 1358 AN: 43466

Ashkenazi Jewish (ASJ) AF: 0.0683 AC: 1722 AN: 25214

East Asian (EAS) AF: 0.0000256 AC: 1 AN: 39078

South Asian (SAS) AF: 0.0301 AC: 2478 AN: 82252

European-Finnish (FIN) AF: 0.0105 AC: 530 AN: 50444

Middle Eastern (MID) AF: 0.0803 AC: 441 AN: 5490

European-Non Finnish (NFE) AF: 0.0377 AC: 37758 AN: 1000634

Other (OTH) AF: 0.0395 AC: 2212 AN: 56026

GnomAD4 genome AF: 0.0424 AC: 6428 AN: 151516 Hom.: 185 Cov.: 22 AF XY: 0.0398 AC XY: 2951 AN XY: 74086

African (AFR) AF: 0.0503 AC: 2080 AN: 41322

American (AMR) AF: 0.0405 AC: 614 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.0764 AC: 265 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.0337 AC: 161 AN: 4784

European-Finnish (FIN) AF: 0.00813 AC: 85 AN: 10454

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 292

European-Non Finnish (NFE) AF: 0.0424 AC: 2880 AN: 67856

Other (OTH) AF: 0.0462 AC: 97 AN: 2100

Alfa AF: 0.0225 Hom.: 16

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

May 24, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.1
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: rs11464745; hg19: chr2-203384788; COSMIC: COSV65814103; COSMIC: COSV65814103;