NM_001135553.4:c.578C>A

Variant names:

• chr1-46565072-G-T
• rs763445956
• NM_001135553.4:c.578C>A

Variant summary

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

The NM_001135553.4(MKNK1):​c.578C>A​(p.Thr193Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T193I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MKNK1 NM_001135553.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.74
• Publications: 0 publications found

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]

MKNK1-AS1 (HGNC:44129): (MKNK1 antisense RNA 1)

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=0.28063595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKNK1	NM_001135553.4	c.578C>A	p.Thr193Asn	missense_variant	Exon 9 of 13	ENST00000371945.10	NP_001129025.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKNK1	ENST00000371945.10	c.578C>A	p.Thr193Asn	missense_variant	Exon 9 of 13	1	NM_001135553.4	ENSP00000361013.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461878 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	0.0013	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;.;T;.;.;.
Eigen	Benign	0.028
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T;T;T;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.28	T;T;T;T;T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.74	N;.;.;.;.;.;.
PhyloP100		6.7
PrimateAI	Uncertain	0.66	T
REVEL	Benign	0.12
Sift4G	Benign	0.076	.;.;.;T;.;.;.
Polyphen		0.96	D;P;B;B;.;.;.
Vest4		0.37
MutPred		0.36		Loss of glycosylation at T246 (P = 0.0123);.;.;.;.;.;.;
MVP		0.81
MPC		0.76
ClinPred		0.89	D
GERP RS		3.9
PromoterAI		0.0079	Neutral
Varity_R		0.094
gMVP		0.32
Mutation Taster		=44/56	disease causing

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: rs763445956; hg19: chr1-47030744;