Variant 11-64789547-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004579.5(MAP4K2):c.2453G>A(p.Ser818Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000058 in 1,585,386 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

MAP4K2
NM_004579.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.506

Variant links:

Genes affected

MAP4K2 (HGNC:6864): (mitogen-activated protein kinase kinase kinase kinase 2) The protein encoded by this gene is a member of the serine/threonine protein kinase family. Although this kinase is found in many tissues, its expression in lymphoid follicles is restricted to the cells of germinal centre, where it may participate in B-cell differentiation. This kinase can be activated by TNF-alpha, and has been shown to specifically activate MAP kinases. This kinase is also found to interact with TNF receptor-associated factor 2 (TRAF2), which is involved in the activation of MAP3K1/MEKK1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

MAP4K2 links:

MAP4K2 (HGNC:):

MAP4K2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.01167503).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP4K2	NM_004579.5 linkuse as main transcript	c.2453G>A	p.Ser818Asn	missense_variant	32/32	ENST00000294066.7	NP_004570.2	Q12851-1A0A024R567
MAP4K2	NM_001307990.2 linkuse as main transcript	c.2429G>A	p.Ser810Asn	missense_variant	32/32		NP_001294919.1	Q12851-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP4K2	ENST00000294066.7 linkuse as main transcript	c.2453G>A	p.Ser818Asn	missense_variant	32/32	1	NM_004579.5	ENSP00000294066.2		Q12851-1

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000833

AC:

AN:

204014

Hom.:

AF XY:

0.0000732

AC XY:

AN XY:

109342

show subpopulations

Gnomad AFR exome

AF:

0.00128

Gnomad AMR exome

AF:

0.0000345

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000321

AC:

AN:

1433202

Hom.:

Cov.:

AF XY:

0.0000310

AC XY:

AN XY:

709988

show subpopulations

Gnomad4 AFR exome

AF:

0.00118

Gnomad4 AMR exome

AF:

0.0000252

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:

0.00

Gnomad4 OTH exome

AF:

0.000101

GnomAD4 genome

AF:

0.000302

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00109

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000248

Hom.:

Bravo

AF:

0.000382

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000744

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

Apr 11, 2023

The c.2453G>A (p.S818N) alteration is located in exon 32 (coding exon 32) of the MAP4K2 gene. This alteration results from a G to A substitution at nucleotide position 2453, causing the serine (S) at amino acid position 818 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

Benign

0.16

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.36

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.0099

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.0

L;.

PrimateAI

Uncertain

0.52

PROVEAN

Benign

0.73

N;N

REVEL

Benign

0.080

Sift

Benign

1.0

T;T

Sift4G

Benign

0.84

T;T

Polyphen

0.11

B;.

Vest4

0.15

MVP

0.70

MPC

0.35

ClinPred

0.020

GERP RS

3.3

Varity_R

0.044

gMVP

0.32

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