1-46562719-T-C

Variant names:

• chr1-46562719-T-C
• NM_001135553.4:c.734A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001135553.4(MKNK1):​c.734A>G​(p.Tyr245Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000764 in 1,439,374 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: MKNK1 NM_001135553.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.47
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MKNK1	NM_001135553.4	c.734A>G	p.Tyr245Cys	missense_variant	Exon 10 of 13	ENST00000371945.10	NP_001129025.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MKNK1	ENST00000371945.10	c.734A>G	p.Tyr245Cys	missense_variant	Exon 10 of 13	1	NM_001135553.4	ENSP00000361013.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000764 AC: 11 AN: 1439374 Hom.: 0 Cov.: 31 AF XY: 0.00000561 AC XY: 4 AN XY: 713626

African (AFR) AF: 0.0000301 AC: 1 AN: 33206

American (AMR) AF: 0.00 AC: 0 AN: 41482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25626

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38964

South Asian (SAS) AF: 0.00 AC: 0 AN: 83242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000818 AC: 9 AN: 1099968

Other (OTH) AF: 0.00 AC: 0 AN: 59510

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.893A>G (p.Y298C) alteration is located in exon 11 (coding exon 10) of the MKNK1 gene. This alteration results from a A to G substitution at nucleotide position 893, causing the tyrosine (Y) at amino acid position 298 to be replaced by a cysteine (C). 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	0.17
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.;.;T;.;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	0.46	N;.;.;.;.;.;.
PhyloP100		4.5
PrimateAI	Uncertain	0.72	T
REVEL	Uncertain	0.43
Sift4G	Uncertain	0.0050	.;.;.;D;.;.;.
Polyphen		1.0	D;D;D;D;.;.;.
Vest4		0.39
MutPred		0.66		Loss of glycosylation at S296 (P = 0.2498);.;.;.;.;.;.;
MVP		0.86
MPC		0.56
ClinPred		0.92	D
GERP RS		5.4
Varity_R		0.76
gMVP		0.80
Mutation Taster		=42/58	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

hg19: chr1-47028391;