rs748162903

Variant names:

• chr19-2039618-C-A
• rs748162903
• NM_199054.3:c.1393G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-2039618-C-A
• chr19-2039618-C-G
• chr19-2039618-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_199054.3(MKNK2):​c.1393G>T​(p.Ala465Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A465T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MKNK2 NM_199054.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.48
• Publications: 2 publications found

Genes affected

MKNK2 (HGNC:7111): (MAPK interacting serine/threonine kinase 2) This gene encodes a member of the calcium/calmodulin-dependent protein kinases (CAMK) Ser/Thr protein kinase family, which belongs to the protein kinase superfamily. This protein contains conserved DLG (asp-leu-gly) and ENIL (glu-asn-ile-leu) motifs, and an N-terminal polybasic region which binds importin A and the translation factor scaffold protein eukaryotic initiation factor 4G (eIF4G). This protein is one of the downstream kinases activated by mitogen-activated protein (MAP) kinases. It phosphorylates the eukaryotic initiation factor 4E (eIF4E), thus playing important roles in the initiation of mRNA translation, oncogenic transformation and malignant cell proliferation. In addition to eIF4E, this protein also interacts with von Hippel-Lindau tumor suppressor (VHL), ring-box 1 (Rbx1) and Cullin2 (Cul2), which are all components of the CBC(VHL) ubiquitin ligase E3 complex. Multiple alternatively spliced transcript variants have been found, but the full-length nature and biological activity of only two variants are determined. These two variants encode distinct isoforms which differ in activity and regulation, and in subcellular localization. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30722368).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199054.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKNK2	NM_199054.3	MANE Select	c.1393G>T	p.Ala465Ser	missense	Exon 14 of 14	NP_951009.1	Q9HBH9-1
	MKNK2	NM_017572.4		c.1154+516G>T		intron	N/A	NP_060042.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKNK2	ENST00000250896.9	TSL:5 MANE Select	c.1393G>T	p.Ala465Ser	missense	Exon 14 of 14	ENSP00000250896.3	Q9HBH9-1
	MKNK2	ENST00000309340.11	TSL:1	c.1154+516G>T		intron	N/A	ENSP00000309485.6	Q9HBH9-2
	MKNK2	ENST00000907126.1		c.1420G>T	p.Ala474Ser	missense	Exon 13 of 13	ENSP00000577185.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	T
Eigen	Benign	0.085
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.54	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.5
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.31
MutPred		0.22		Gain of phosphorylation at A465 (P = 0.0472)
MVP		0.83
MPC		0.14
ClinPred		0.70	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.27
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs748162903; hg19: chr19-2039617;