17-21300880-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BP4_Strong

The NM_145109.3(MAP2K3):c.286C>T(p.Arg96Trp) variant causes a missense change. 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.50 (0 hom., cov: 67)
  • Exomes 𝑓: 0.50 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAP2K3 NM_145109.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.72

Genes affected

MAP2K3 (HGNC:6843): (mitogen-activated protein kinase kinase 3) The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase is activated by mitogenic and environmental stress, and participates in the MAP kinase-mediated signaling cascade. It phosphorylates and thus activates MAPK14/p38-MAPK. This kinase can be activated by insulin, and is necessary for the expression of glucose transporter. Expression of RAS oncogene is found to result in the accumulation of the active form of this kinase, which thus leads to the constitutive activation of MAPK14, and confers oncogenic transformation of primary cells. The inhibition of this kinase is involved in the pathogenesis of Yersina pseudotuberculosis. Multiple alternatively spliced transcript variants that encode distinct isoforms have been reported for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, PrimateAI, PROVEAN [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.0043037534).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K3	NM_145109.3	c.286C>T	p.Arg96Trp	missense_variant	5/12	ENST00000342679.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K3	ENST00000342679.9	c.286C>T	p.Arg96Trp	missense_variant	5/12	1	NM_145109.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 76153 AN: 152306 Hom.: 0 Cov.: 67 FAILED QC

Gnomad AFR AF: 0.500

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.500

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.500

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.498 AC: 695652 AN: 1395920 Hom.: 0 Cov.: 105 AF XY: 0.499 AC XY: 347436 AN XY: 696906

Gnomad4 AFR exome AF: 0.498

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.499

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.499

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.498

Gnomad4 OTH exome AF: 0.499

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.500 AC: 76212 AN: 152424 Hom.: 0 Cov.: 67 AF XY: 0.500 AC XY: 37271 AN XY: 74542

Gnomad4 AFR AF: 0.500

Gnomad4 AMR AF: 0.500

Gnomad4 ASJ AF: 0.500

Gnomad4 EAS AF: 0.500

Gnomad4 SAS AF: 0.500

Gnomad4 FIN AF: 0.500

Gnomad4 NFE AF: 0.500

Gnomad4 OTH AF: 0.500

Alfa AF: 0.493 Hom.: 2

ExAC AF: 0.500 AC: 60660

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hepatocellular carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

research

Arun Kumar Laboratory, Indian Institute of Science

Jun 15, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Pathogenic	33
Dann	Uncertain	0.99
DEOGEN2	Benign	0.40	T;T;.;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	D;D;D;.;.
MetaRNN	Benign	0.0043	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.9	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.9	D;D;D;.;.
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;D;D;.;.
Sift4G	Uncertain	0.043	D;D;T;T;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.70
MPC		0.61
ClinPred		0.038	T
GERP RS		5.1
Varity_R		0.88
gMVP		0.72

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

LitVar

Other links and lift over

dbSNP: rs56216806; hg19: chr17-21204192; COSMIC: COSV57561406; COSMIC: COSV57561406;