17-21300581-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_145109.3(MAP2K3):c.202T>C(p.Ser68Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). 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: 68)
  • Exomes 𝑓: 0.50 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAP2K3 NM_145109.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.50

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002731979).
• BP6: Variant 17-21300581-T-C is Benign according to our data. Variant chr17-21300581-T-C is described in ClinVar as [Benign]. Clinvar id is 768844.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.202T>C	p.Ser68Pro	missense_variant	4/12	ENST00000342679.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K3	ENST00000342679.9	c.202T>C	p.Ser68Pro	missense_variant	4/12	1	NM_145109.3	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 76104 AN: 152214 Hom.: 0 Cov.: 68 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: 0.497 AC: 697665 AN: 1404720 Hom.: 3 Cov.: 85 AF XY: 0.497 AC XY: 347658 AN XY: 699582

Gnomad4 AFR exome AF: 0.494

Gnomad4 AMR exome AF: 0.499

Gnomad4 ASJ exome AF: 0.498

Gnomad4 EAS exome AF: 0.499

Gnomad4 SAS exome AF: 0.499

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.496

Gnomad4 OTH exome AF: 0.497

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.500 AC: 76163 AN: 152332 Hom.: 0 Cov.: 68 AF XY: 0.500 AC XY: 37244 AN XY: 74492

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: 0.483 AC: 58589

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

Jun 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;.;.;.
Eigen	Benign	-0.017
Eigen_PC	Benign	0.038
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.45	T;T;T;.;.
MetaRNN	Benign	0.0027	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.6	N;N;N;.;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.018	D;T;D;.;.
Sift4G	Benign	0.082	T;T;T;T;T
Polyphen		0.27	B;.;.;.;.
Vest4		0.43
MPC		0.20
ClinPred		0.025	T
GERP RS		5.5
Varity_R		0.76
gMVP		0.77

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: rs34105301; hg19: chr17-21203893; COSMIC: COSV57561381; COSMIC: COSV57561381;