22-50267933-G-A

Position:

• chr22-50267933-G-A

Variant summary

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

The ENST00000330651.11(MAPK11):​c.133C>T​(p.Arg45Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,422,156 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MAPK11 ENST00000330651.11 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43

Genes affected

MAPK11 (HGNC:6873): (mitogen-activated protein kinase 11) This gene encodes a member of a family of protein kinases that are involved in the integration of biochemical signals for a wide variety of cellular processes, including cell proliferation, differentiation, transcriptional regulation, and development. The encoded protein can be activated by proinflammatory cytokines and environmental stresses through phosphorylation by mitogen activated protein kinase kinases (MKKs). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPK11	NM_002751.7	c.133C>T	p.Arg45Trp	missense_variant	2/12	ENST00000330651.11	NP_002742.3
MAPK11	NR_110887.2	n.221C>T		non_coding_transcript_exon_variant	2/13
MAPK11	XM_047441447.1			upstream_gene_variant			XP_047297403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPK11	ENST00000330651.11	c.133C>T	p.Arg45Trp	missense_variant	2/12	1	NM_002751.7	ENSP00000333685	P1
MAPK11	ENST00000395764.5	c.133C>T	p.Arg45Trp	missense_variant, NMD_transcript_variant	2/13	1		ENSP00000379113
MAPK11	ENST00000495277.1	n.192C>T		non_coding_transcript_exon_variant	2/4	4
MAPK11	ENST00000417877.1	c.133C>T	p.Arg45Trp	missense_variant, NMD_transcript_variant	2/12	5		ENSP00000409136

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1422156 Hom.: 0 Cov.: 38 AF XY: 0.00000284 AC XY: 2 AN XY: 705354

Gnomad4 AFR exome AF: 0.0000333

Gnomad4 AMR exome AF: 0.00

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: 9.13e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000845 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

The c.133C>T (p.R45W) alteration is located in exon 2 (coding exon 2) of the MAPK11 gene. This alteration results from a C to T substitution at nucleotide position 133, causing the arginine (R) at amino acid position 45 to be replaced by a tryptophan (W). 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	0.18
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.11
Eigen_PC	Benign	-0.043
FATHMM_MKL	Benign	0.21	N
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.13
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.046	D
Polyphen		0.99	D
Vest4		0.35
MutPred		0.32		Loss of solvent accessibility (P = 0.0217);
MVP		0.80
MPC		2.1
ClinPred		0.89	D
GERP RS		3.7
Varity_R		0.41
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs751375132; hg19: chr22-50706362;