4-78842495-T-C

Position:

• chr4-78842495-T-C

Variant summary

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

The NM_198892.2(BMP2K):​c.514T>C​(p.Cys172Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000901 in 1,442,606 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: BMP2K NM_198892.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.23

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP2K	NM_198892.2	c.514T>C	p.Cys172Arg	missense_variant	4/16	ENST00000502613.3	NP_942595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMP2K	ENST00000502613.3	c.514T>C	p.Cys172Arg	missense_variant	4/16	1	NM_198892.2	ENSP00000424668.2
BMP2K	ENST00000502871.5	c.514T>C	p.Cys172Arg	missense_variant	4/14	1		ENSP00000421768.1
BMP2K	ENST00000389010.7	n.514T>C		non_coding_transcript_exon_variant	4/15	1		ENSP00000373662.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000901 AC: 13 AN: 1442606 Hom.: 0 Cov.: 30 AF XY: 0.00000837 AC XY: 6 AN XY: 716718

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000118

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

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

Sep 30, 2024

The c.514T>C (p.C172R) alteration is located in exon 4 (coding exon 4) of the BMP2K gene. This alteration results from a T to C substitution at nucleotide position 514, causing the cysteine (C) at amino acid position 172 to be replaced by an arginine (R). 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	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Benign	0.86
DEOGEN2	Benign	0.071	.;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.050
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-0.12	N;N;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-9.8	D;D;.
REVEL	Uncertain	0.46
Sift	Benign	0.086	T;D;.
Sift4G	Benign	0.18	T;T;T
Polyphen		0.39	.;B;.
Vest4		0.84
MutPred		0.50		Gain of disorder (P = 0.0138);Gain of disorder (P = 0.0138);Gain of disorder (P = 0.0138);
MVP		0.50
MPC		0.36
ClinPred		0.43	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.76

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: rs1375384213; hg19: chr4-79763649;