NM_198892.2:c.2146C>A

Variant names:

• chr4-78910693-C-A
• rs188481381
• NM_198892.2:c.2146C>A

Variant summary

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

The NM_198892.2(BMP2K):​c.2146C>A​(p.Pro716Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BMP2K NM_198892.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.06

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]

PAQR3 (HGNC:30130): (progestin and adipoQ receptor family member 3) This gene encodes a seven-transmembrane protein localized in the Golgi apparatus in mammalian cells. The encoded protein belongs to the progestin and adipoQ receptor (PAQR) family. This protein functions as a tumor suppressor by inhibiting the Raf/MEK/ERK signaling cascade. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2017]

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=0.15110487).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP2K	NM_198892.2	c.2146C>A	p.Pro716Thr	missense_variant	Exon 16 of 16	ENST00000502613.3	NP_942595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP2K	ENST00000502613.3	c.2146C>A	p.Pro716Thr	missense_variant	Exon 16 of 16	1	NM_198892.2	ENSP00000424668.2
PAQR3	ENST00000342820.10	n.*782+4517G>T		intron_variant	Intron 10 of 12	1		ENSP00000344203.6
PAQR3	ENST00000512760.5	n.*792+4517G>T		intron_variant	Intron 7 of 8	1		ENSP00000426875.1
PAQR3	ENST00000511594.5	n.*1496G>T		downstream_gene_variant		5		ENSP00000425080.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000814 AC: 2 AN: 245776 Hom.: 0 AF XY: 0.00000751 AC XY: 1 AN XY: 133178

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000590

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458820 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725502

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000453

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	13
DANN	Benign	0.69
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.9	L
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.20
Sift	Benign	0.032	D
Sift4G	Benign	0.60	T
Polyphen		0.20	B
Vest4		0.066
MutPred		0.18		Loss of glycosylation at P716 (P = 0.0364);
MVP		0.76
MPC		0.089
ClinPred		0.073	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.064
gMVP		0.052

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs188481381; hg19: chr4-79831847;