Genetic Variant MAP2K5:p.Met432Val (chr15-67806697-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_145160.3(MAP2K5):c.1294A>G(p.Met432Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,399,650 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MAP2K5
NM_145160.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.84

Publications

0 publications found

Variant links:

Genes affected

MAP2K5 (HGNC:6845): (mitogen-activated protein kinase kinase 5) The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase specifically interacts with and activates MAPK7/ERK5. This kinase itself can be phosphorylated and activated by MAP3K3/MEKK3, as well as by atypical protein kinase C isoforms (aPKCs). The signal cascade mediated by this kinase is involved in growth factor stimulated cell proliferation and muscle cell differentiation. Three alternatively spliced transcript variants of this gene encoding distinct isoforms have been described. [provided by RefSeq, May 2011]

MAP2K5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145160.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAP2K5	NM_145160.3	MANE Select	c.1294A>G	p.Met432Val	missense	Exon 22 of 22	NP_660143.1	Q13163-1
MAP2K5	NM_002757.4		c.1264A>G	p.Met422Val	missense	Exon 21 of 21	NP_002748.1	Q13163-2
MAP2K5	NM_001206804.2		c.1186A>G	p.Met396Val	missense	Exon 22 of 22	NP_001193733.1	Q13163-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAP2K5	ENST00000178640.10	TSL:1 MANE Select	c.1294A>G	p.Met432Val	missense	Exon 22 of 22	ENSP00000178640.5	Q13163-1
MAP2K5	ENST00000395476.6	TSL:1	c.1264A>G	p.Met422Val	missense	Exon 21 of 21	ENSP00000378859.2	Q13163-2
MAP2K5	ENST00000952141.1		c.1465A>G	p.Met489Val	missense	Exon 24 of 24	ENSP00000622200.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1399650

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690506

show subpopulations

African (AFR)

AF:

0.0000631

AC:

AN:

31676

American (AMR)

AF:

0.00

AC:

AN:

35866

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25186

East Asian (EAS)

AF:

0.00

AC:

AN:

35852

South Asian (SAS)

AF:

0.00

AC:

AN:

79322

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079666

Other (OTH)

AF:

0.00

AC:

AN:

58060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000374

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.089

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.3

PhyloP100

7.8

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.65

REVEL

Uncertain

0.38

Sift

Benign

0.094

Sift4G

Benign

0.33

Polyphen

0.61

Vest4

0.87

MVP

0.76

MPC

1.1

ClinPred

0.72

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.41

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over