NM_001200.4:c.-7-2_-7-1delAGinsCC

Variant names:

• chr20-6770118-AG-CC
• rs1600170070
• NM_001200.4:c.-7-2_-7-1delAGinsCC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_001200.4(BMP2):​c.-7-2_-7-1delAGinsCC variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BMP2 NM_001200.4 splice_acceptor, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.17
• 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 9 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.7, offset of 35, new splice context is: cgggacccgctgtcttctAGcgt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP5: Variant 20-6770118-AG-CC is Pathogenic according to our data. Variant chr20-6770118-AG-CC is described in ClinVar as Pathogenic. ClinVar VariationId is 492936.Status of the report is no_assertion_criteria_provided, 0 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.-7-2_-7-1delAGinsCC		splice_acceptor intron	N/A	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.-7-2_-7-1delAGinsCC		splice_acceptor intron	N/A	ENSP00000368104.3	P12643
	BMP2	ENST00000936876.1		c.-9_-8delAGinsCC		5_prime_UTR	Exon 1 of 2	ENSP00000606935.1
	BMP2	ENST00000953442.1		c.-7-2_-7-1delAGinsCC		splice_acceptor intron	N/A	ENSP00000623501.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
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
PhyloP100		6.2
Mutation Taster		=2/98	disease causing

Splicing

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

Other links and lift over

dbSNP: rs1600170070; hg19: chr20-6750765;