rs1555786156

Variant names:

• chr20-6778885-C-A
• rs1555786156
• NM_001200.4:c.987C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001200.4(BMP2):​c.987C>A​(p.Cys329*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BMP2 NM_001200.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.855
• Publications: 0 publications found

Genes affected

BMP2 (HGNC:1069): (bone morphogenetic protein 2) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer, which plays a role in bone and cartilage development. Duplication of a regulatory region downstream of this gene causes a form of brachydactyly characterized by a malformed index finger and second toe in human patients. [provided by RefSeq, Jul 2016]

BMP2 Gene-Disease associations (from GenCC):

• short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• brachydactyly type A2

  Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-6778885-C-A is Pathogenic according to our data. Variant chr20-6778885-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 492937.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001200.4. 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
	BMP2	NM_001200.4	MANE Select	c.987C>A	p.Cys329*	stop_gained	Exon 3 of 3	NP_001191.1	P12643

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP2	ENST00000378827.5	TSL:1 MANE Select	c.987C>A	p.Cys329*	stop_gained	Exon 3 of 3	ENSP00000368104.3	P12643
	BMP2	ENST00000936876.1		c.987C>A	p.Cys329*	stop_gained	Exon 2 of 2	ENSP00000606935.1
	BMP2	ENST00000953442.1		c.987C>A	p.Cys329*	stop_gained	Exon 3 of 3	ENSP00000623501.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies (1)
1	-	-	Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.81	D
PhyloP100		0.85
Vest4		0.86
GERP RS		-0.41
Mutation Taster		=1/199	disease causing (ClinVar)

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: rs1555786156; hg19: chr20-6759532;