1-46561485-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001135553.4(MKNK1):ā€‹c.962T>Cā€‹(p.Val321Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

MKNK1
NM_001135553.4 missense

Scores

3
8
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.11
Variant links:
Genes affected
MKNK1 (HGNC:7110): (MAPK interacting serine/threonine kinase 1) This gene encodes a Ser/Thr protein kinase that interacts with, and is activated by ERK1 and p38 mitogen-activated protein kinases, and thus may play a role in the response to environmental stress and cytokines. This kinase may also regulate transcription by phosphorylating eIF4E via interaction with the C-terminal region of eIF4G. Alternatively spliced transcript variants have been noted for this gene. [provided by RefSeq, Jan 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.869

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MKNK1NM_001135553.4 linkuse as main transcriptc.962T>C p.Val321Ala missense_variant 11/13 ENST00000371945.10 NP_001129025.2 Q9BUB5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MKNK1ENST00000371945.10 linkuse as main transcriptc.962T>C p.Val321Ala missense_variant 11/131 NM_001135553.4 ENSP00000361013.5 A0A499FJN1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000160
AC:
4
AN:
250014
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135096
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000872
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:
0.00000886
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1459978
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
726140
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000673
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:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 21, 2022The c.1121T>C (p.V374A) alteration is located in exon 12 (coding exon 11) of the MKNK1 gene. This alteration results from a T to C substitution at nucleotide position 1121, causing the valine (V) at amino acid position 374 to be replaced by an alanine (A). 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
0.90
BayesDel_addAF
Benign
-0.065
T
BayesDel_noAF
Benign
-0.13
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.46
T;.;.;T;.;.;.
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.65
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.91
D;D;D;D;D;D;D
M_CAP
Benign
0.0078
T
MetaRNN
Pathogenic
0.87
D;D;D;D;D;D;D
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.8
L;.;.;.;.;.;.
PrimateAI
Uncertain
0.59
T
REVEL
Uncertain
0.36
Sift4G
Uncertain
0.0040
.;.;.;D;.;.;.
Polyphen
0.93
P;P;P;P;.;.;.
Vest4
0.70
MutPred
0.80
Gain of disorder (P = 0.0332);.;.;.;.;.;.;
MVP
0.42
MPC
0.63
ClinPred
0.88
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.94
gMVP
0.73

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs767281602; hg19: chr1-47027157; API