4-78865591-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198892.2(BMP2K):c.1102A>G(p.Ile368Val) variant causes a missense change. The variant allele was found at a frequency of 0.00017 in 1,614,100 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: BMP2K NM_198892.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.60

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.071587116).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP2K	NM_198892.2	c.1102A>G	p.Ile368Val	missense_variant	10/16	ENST00000502613.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP2K	ENST00000502613.3	c.1102A>G	p.Ile368Val	missense_variant	10/16	1	NM_198892.2	P1
BMP2K	ENST00000502871.5	c.1102A>G	p.Ile368Val	missense_variant	10/14	1
BMP2K	ENST00000389010.7	c.*78A>G		3_prime_UTR_variant, NMD_transcript_variant	11/15	1
BMP2K	ENST00000505725.1	n.384A>G		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000239 AC: 60 AN: 251374 Hom.: 1 AF XY: 0.000258 AC XY: 35 AN XY: 135852

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000161 AC: 235 AN: 1461812 Hom.: 1 Cov.: 30 AF XY: 0.000169 AC XY: 123 AN XY: 727206

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000348

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000128

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74466

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000334 Hom.: 1

Bravo AF: 0.000298

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2024

The c.1102A>G (p.I368V) alteration is located in exon 10 (coding exon 10) of the BMP2K gene. This alteration results from a A to G substitution at nucleotide position 1102, causing the isoleucine (I) at amino acid position 368 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.072	T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.57	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.21	T;T
Sift4G	Benign	0.62	T;T
Polyphen		0.086	.;B
Vest4		0.48
MVP		0.84
MPC		0.092
ClinPred		0.029	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.088
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs147699895; hg19: chr4-79786745; COSMIC: COSV58597988; COSMIC: COSV58597988;