22-50266585-T-C

Position:

• chr22-50266585-T-C

Variant summary

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

The NM_002751.7(MAPK11):​c.637A>G​(p.Met213Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,372,758 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: 0.0000015 (0 hom.)
• Consequence: MAPK11 NM_002751.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.478

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]

MAPK11 (HGNC:):

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.637A>G	p.Met213Val	missense_variant	8/12	ENST00000330651.11	NP_002742.3
MAPK11	XM_047441447.1	c.313A>G	p.Met105Val	missense_variant	6/10		XP_047297403.1
MAPK11	NR_110887.2	n.725A>G		non_coding_transcript_exon_variant	8/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPK11	ENST00000330651.11	c.637A>G	p.Met213Val	missense_variant	8/12	1	NM_002751.7	ENSP00000333685.6
MAPK11	ENST00000395764.5	n.637A>G		non_coding_transcript_exon_variant	8/13	1		ENSP00000379113.1
MAPK11	ENST00000417877.1	n.*149A>G		non_coding_transcript_exon_variant	8/12	5		ENSP00000409136.1
MAPK11	ENST00000417877.1	n.*149A>G		3_prime_UTR_variant	8/12	5		ENSP00000409136.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1372758 Hom.: 0 Cov.: 32 AF XY: 0.00000297 AC XY: 2 AN XY: 673476

Gnomad4 AFR exome AF: 0.00

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: 0.00000187

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Aug 23, 2021

The c.637A>G (p.M213V) alteration is located in exon 8 (coding exon 8) of the MAPK11 gene. This alteration results from a A to G substitution at nucleotide position 637, causing the methionine (M) at amino acid position 213 to be replaced by a valine (V). 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	Uncertain	0.35
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.094
Eigen_PC	Benign	0.016
FATHMM_MKL	Benign	0.61	D
M_CAP	Uncertain	0.085	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.94	L
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.021	D
Polyphen		0.33	B
Vest4		0.63
MutPred		0.76		Gain of catalytic residue at M213 (P = 0.052);
MVP		0.67
MPC		0.38
ClinPred		0.97	D
GERP RS		4.3
Varity_R		0.84
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-50705014;