22-50265630-T-G

Position:

• chr22-50265630-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002751.7(MAPK11):​c.793A>C​(p.Met265Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MAPK11 NM_002751.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12836984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPK11	NM_002751.7	c.793A>C	p.Met265Leu	missense_variant	10/12	ENST00000330651.11	NP_002742.3
MAPK11	XM_047441447.1	c.469A>C	p.Met157Leu	missense_variant	8/10		XP_047297403.1
MAPK11	NR_110887.2	n.881A>C		non_coding_transcript_exon_variant	10/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPK11	ENST00000330651.11	c.793A>C	p.Met265Leu	missense_variant	10/12	1	NM_002751.7	ENSP00000333685.6
MAPK11	ENST00000395764.5	n.793A>C		non_coding_transcript_exon_variant	10/13	1		ENSP00000379113.1
MAPK11	ENST00000417877.1	n.*305A>C		non_coding_transcript_exon_variant	10/12	5		ENSP00000409136.1
MAPK11	ENST00000417877.1	n.*305A>C		3_prime_UTR_variant	10/12	5		ENSP00000409136.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449540 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 720074

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: 9.04e-7

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

Sep 17, 2021

The c.793A>C (p.M265L) alteration is located in exon 10 (coding exon 10) of the MAPK11 gene. This alteration results from a A to C substitution at nucleotide position 793, causing the methionine (M) at amino acid position 265 to be replaced by a leucine (L). 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	0.099
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.68	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.30
Sift	Benign	0.36	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.41
MutPred		0.36		Loss of methylation at K268 (P = 0.0887);
MVP		0.23
MPC		0.24
ClinPred		0.68	D
GERP RS		4.3
Varity_R		0.68
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: chr22-50704059;