chr4-78833624-T-A

Position:

• chr4-78833624-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_198892.2(BMP2K):​c.340T>A​(p.Cys114Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BMP2K NM_198892.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.03

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.342081).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BMP2K	NM_198892.2	c.340T>A	p.Cys114Ser	missense_variant	3/16	ENST00000502613.3	NP_942595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BMP2K	ENST00000502613.3	c.340T>A	p.Cys114Ser	missense_variant	3/16	1	NM_198892.2	ENSP00000424668	P1
BMP2K	ENST00000502871.5	c.340T>A	p.Cys114Ser	missense_variant	3/14	1		ENSP00000421768
BMP2K	ENST00000389010.7	c.340T>A	p.Cys114Ser	missense_variant, NMD_transcript_variant	3/15	1		ENSP00000373662

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453518 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 722876

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: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 01, 2023

The c.340T>A (p.C114S) alteration is located in exon 3 (coding exon 3) of the BMP2K gene. This alteration results from a T to A substitution at nucleotide position 340, causing the cysteine (C) at amino acid position 114 to be replaced by a serine (S). 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	0.23
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.52
DEOGEN2	Benign	0.012	.;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.047
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.52	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.12	N;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.45	N;N;.
REVEL	Benign	0.20
Sift	Benign	1.0	T;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.050	.;B;.
Vest4		0.40
MutPred		0.82		Loss of catalytic residue at S118 (P = 0.022);Loss of catalytic residue at S118 (P = 0.022);Loss of catalytic residue at S118 (P = 0.022);
MVP		0.44
MPC		0.11
ClinPred		0.36	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-79754778;