NM_198892.2:c.691G>A

Variant names:

• chr4-78847210-G-A
• rs777127820
• NM_198892.2:c.691G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_198892.2(BMP2K):​c.691G>A​(p.Ala231Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. A231S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BMP2K NM_198892.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.59
• Publications: 0 publications found

Genes affected

BMP2K (HGNC:18041): (BMP2 inducible kinase) This gene is the human homolog of mouse BMP-2-inducible kinase. Bone morphogenic proteins (BMPs) play a key role in skeletal development and patterning. Expression of the mouse gene is increased during BMP-2 induced differentiation and the gene product is a putative serine/threonine protein kinase containing a nuclear localization signal. Therefore, the protein encoded by this human homolog is thought to be a protein kinase with a putative regulatory role in attenuating the program of osteoblast differentiation. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198892.2. 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
	BMP2K	NM_198892.2	MANE Select	c.691G>A	p.Ala231Thr	missense	Exon 6 of 16	NP_942595.1	Q9NSY1-1
	BMP2K	NM_001419799.1		c.691G>A	p.Ala231Thr	missense	Exon 6 of 15	NP_001406728.1
	BMP2K	NM_001419800.1		c.691G>A	p.Ala231Thr	missense	Exon 6 of 16	NP_001406729.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BMP2K	ENST00000502613.3	TSL:1 MANE Select	c.691G>A	p.Ala231Thr	missense	Exon 6 of 16	ENSP00000424668.2	Q9NSY1-1
	BMP2K	ENST00000502871.5	TSL:1	c.691G>A	p.Ala231Thr	missense	Exon 6 of 14	ENSP00000421768.1	Q9NSY1-2
	BMP2K	ENST00000389010.7	TSL:1	n.691G>A		non_coding_transcript_exon	Exon 6 of 15	ENSP00000373662.3	K4DI97

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000835 AC: 2 AN: 239430 AF XY: 0.00000767

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000182

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1431644 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 712812

African (AFR) AF: 0.00 AC: 0 AN: 32186

American (AMR) AF: 0.00 AC: 0 AN: 41602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25324

East Asian (EAS) AF: 0.00 AC: 0 AN: 38268

South Asian (SAS) AF: 0.00 AC: 0 AN: 82250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1095432

Other (OTH) AF: 0.00 AC: 0 AN: 58610

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000255 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.074	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		6.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.51
Sift	Benign	0.050	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.89		Gain of glycosylation at Y229 (P = 0.1789)
MVP		0.56
MPC		0.44
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.50
gMVP		0.86
Mutation Taster		=47/53	disease causing

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: rs777127820; hg19: chr4-79768364;