Variant 2-127326727-A-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3BP4_ModerateBS2

The NM_001371910.2(MAP3K2):c.557T>A(p.Ile186Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000567 in 1,606,428 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00058 ( 2 hom. )

Consequence

MAP3K2
NM_001371910.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.00

Variant links:

Genes affected

MAP3K2 (HGNC:6854): (mitogen-activated protein kinase kinase kinase 2) The protein encoded by this gene is a member of serine/threonine protein kinase family. This kinase preferentially activates other kinases involved in the MAP kinase signaling pathway. This kinase has been shown to directly phosphorylate and activate Ikappa B kinases, and thus plays a role in NF-kappa B signaling pathway. This kinase has also been found to bind and activate protein kinase C-related kinase 2, which suggests its involvement in a regulated signaling process. [provided by RefSeq, Jul 2008]

MAP3K2 links:

ENSG00000286145 (HGNC:):

ENSG00000286145 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, MutationAssessor, phyloP100way_vertebrate, PrimateAI [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.12255633).

BS2

High AC in GnomAd4 at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP3K2	NM_001371910.2 linkuse as main transcript	c.557T>A	p.Ile186Asn	missense_variant	8/17	ENST00000682094.1	NP_001358839.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP3K2	ENST00000682094.1 linkuse as main transcript	c.557T>A	p.Ile186Asn	missense_variant	8/17		NM_001371910.2	ENSP00000507315.1		Q9Y2U5

Frequencies

GnomAD3 genomes

AF:

0.000473

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000563

AC:

138

AN:

245054

Hom.:

AF XY:

0.000586

AC XY:

AN XY:

133066

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.000334

Gnomad ASJ exome

AF:

0.00522

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000233

Gnomad NFE exome

AF:

0.000580

Gnomad OTH exome

AF:

0.000507

GnomAD4 exome

AF:

0.000577

AC:

839

AN:

1454126

Hom.:

Cov.:

AF XY:

0.000590

AC XY:

427

AN XY:

723500

show subpopulations

Gnomad4 AFR exome

AF:

0.0000602

Gnomad4 AMR exome

AF:

0.000370

Gnomad4 ASJ exome

AF:

0.00400

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000733

Gnomad4 NFE exome

AF:

0.000581

Gnomad4 OTH exome

AF:

0.000567

GnomAD4 genome

AF:

0.000473

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000759

Hom.:

Bravo

AF:

0.000529

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000978

AC:

ExAC

AF:

0.000588

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2021

The c.557T>A (p.I186N) alteration is located in exon 7 (coding exon 7) of the MAP3K2 gene. This alteration results from a T to A substitution at nucleotide position 557, causing the isoleucine (I) at amino acid position 186 to be replaced by an asparagine (N). 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

Pathogenic

0.82

BayesDel_addAF

Uncertain

0.066

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

D;D

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Uncertain

0.085

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-0.38

MutationAssessor

Pathogenic

3.0

M;M

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.4

D;D

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.99

D;D

Vest4

0.85

MVP

0.83

MPC

1.4

ClinPred

0.10

GERP RS

5.7

Varity_R

0.90

gMVP

0.80

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over