17-21304522-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3 BP4_Strong BP6_Moderate

The NM_145109.3(MAP2K3):c.665C>T(p.Thr222Met) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.30 (0 hom., cov: 69)
  • Exomes 𝑓: 0.26 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAP2K3 NM_145109.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.81

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 -5 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, PrimateAI, PROVEAN [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.005416125).
• BP6: Variant 17-21304522-C-T is Benign according to our data. Variant chr17-21304522-C-T is described in ClinVar as [Benign]. Clinvar id is 768851.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K3	NM_145109.3	c.665C>T	p.Thr222Met	missense_variant	8/12	ENST00000342679.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K3	ENST00000342679.9	c.665C>T	p.Thr222Met	missense_variant	8/12	1	NM_145109.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 41211 AN: 137676 Hom.: 0 Cov.: 69 FAILED QC

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.284

Gnomad SAS AF: 0.260

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.291

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.261 AC: 322360 AN: 1233950 Hom.: 0 Cov.: 95 AF XY: 0.261 AC XY: 161078 AN XY: 616044

Gnomad4 AFR exome AF: 0.383

Gnomad4 AMR exome AF: 0.227

Gnomad4 ASJ exome AF: 0.289

Gnomad4 EAS exome AF: 0.262

Gnomad4 SAS exome AF: 0.253

Gnomad4 FIN exome AF: 0.181

Gnomad4 NFE exome AF: 0.262

Gnomad4 OTH exome AF: 0.276

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.299 AC: 41251 AN: 137790 Hom.: 0 Cov.: 69 AF XY: 0.293 AC XY: 19761 AN XY: 67442

Gnomad4 AFR AF: 0.386

Gnomad4 AMR AF: 0.255

Gnomad4 ASJ AF: 0.305

Gnomad4 EAS AF: 0.284

Gnomad4 SAS AF: 0.261

Gnomad4 FIN AF: 0.171

Gnomad4 NFE AF: 0.280

Gnomad4 OTH AF: 0.292

Alfa AF: 0.309 Hom.: 1676

ExAC AF: 0.294 AC: 35674

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D;D;.;.
MetaRNN	Benign	0.0054	T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.7	D;D;.;.
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Uncertain	0.028	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.89
MPC		0.61
ClinPred		0.020	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.86
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs58609466; hg19: chr17-21207834; COSMIC: COSV57562148; COSMIC: COSV57562148;