rs2288255

Positions:

• chr4-78865702-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_198892.2(BMP2K):​c.1213G>A​(p.Gly405Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0485 in 1,613,836 control chromosomes in the GnomAD database, including 3,126 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.041 (264 hom., cov: 32)
  • Exomes 𝑓: 0.049 (2862 hom.)
• Consequence: BMP2K NM_198892.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.465

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023294091).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP2K	NM_198892.2	c.1213G>A	p.Gly405Ser	missense_variant	10/16	ENST00000502613.3	NP_942595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMP2K	ENST00000502613.3	c.1213G>A	p.Gly405Ser	missense_variant	10/16	1	NM_198892.2	ENSP00000424668.2

Frequencies

GnomAD3 genomes AF: 0.0412 AC: 6259 AN: 152020 Hom.: 266 Cov.: 32

Gnomad AFR AF: 0.00810

Gnomad AMI AF: 0.00659

Gnomad AMR AF: 0.0458

Gnomad ASJ AF: 0.0562

Gnomad EAS AF: 0.214

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0564

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0397

Gnomad OTH AF: 0.0459

GnomAD3 exomes AF: 0.0609 AC: 15299 AN: 251300 Hom.: 833 AF XY: 0.0633 AC XY: 8595 AN XY: 135814

Gnomad AFR exome AF: 0.00732

Gnomad AMR exome AF: 0.0397

Gnomad ASJ exome AF: 0.0595

Gnomad EAS exome AF: 0.223

Gnomad SAS exome AF: 0.0983

Gnomad FIN exome AF: 0.0550

Gnomad NFE exome AF: 0.0405

Gnomad OTH exome AF: 0.0496

GnomAD4 exome AF: 0.0493 AC: 72046 AN: 1461698 Hom.: 2862 Cov.: 31 AF XY: 0.0511 AC XY: 37174 AN XY: 727184

Gnomad4 AFR exome AF: 0.00639

Gnomad4 AMR exome AF: 0.0390

Gnomad4 ASJ exome AF: 0.0586

Gnomad4 EAS exome AF: 0.237

Gnomad4 SAS exome AF: 0.0995

Gnomad4 FIN exome AF: 0.0528

Gnomad4 NFE exome AF: 0.0398

Gnomad4 OTH exome AF: 0.0530

GnomAD4 genome AF: 0.0411 AC: 6255 AN: 152138 Hom.: 264 Cov.: 32 AF XY: 0.0440 AC XY: 3271 AN XY: 74386

Gnomad4 AFR AF: 0.00807

Gnomad4 AMR AF: 0.0458

Gnomad4 ASJ AF: 0.0562

Gnomad4 EAS AF: 0.215

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.0564

Gnomad4 NFE AF: 0.0397

Gnomad4 OTH AF: 0.0450

Alfa AF: 0.0461 Hom.: 370

Bravo AF: 0.0382

TwinsUK AF: 0.0367 AC: 136

ALSPAC AF: 0.0371 AC: 143

ESP6500AA AF: 0.0107 AC: 47

ESP6500EA AF: 0.0392 AC: 337

ExAC AF: 0.0609 AC: 7388

Asia WGS AF: 0.141 AC: 487 AN: 3478

EpiCase AF: 0.0423

EpiControl AF: 0.0416

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	7.9
DANN	Benign	0.68
DEOGEN2	Benign	0.018	.;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.65	T;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.95	N;N
REVEL	Benign	0.27
Sift	Benign	0.31	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.57	.;P
Vest4		0.048
MPC		0.11
ClinPred		0.0043	T
GERP RS		-0.26
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.036
gMVP		0.22

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

Publications

LitVar

Other links and lift over

dbSNP: rs2288255; hg19: chr4-79786856; COSMIC: COSV58592187; COSMIC: COSV58592187;