4-86159413-T-G

Position:

chr4-86159413-T-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_138982.4(MAPK10):c.121A>C(p.Lys41Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000422 in 1,612,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

MAPK10
NM_138982.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.15

Variant links:

Genes affected

MAPK10 (HGNC:6872): (mitogen-activated protein kinase 10) The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as integration points for multiple biochemical signals, and thus are involved in a wide variety of cellular processes, such as proliferation, differentiation, transcription regulation and development. This kinase is specifically expressed in a subset of neurons in the nervous system, and is activated by threonine and tyrosine phosphorylation. Targeted deletion of this gene in mice suggests that it may have a role in stress-induced neuronal apoptosis. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. A recent study provided evidence for translational readthrough in this gene, and expression of an additional C-terminally extended isoform via the use of an alternative in-frame translation termination codon. [provided by RefSeq, Dec 2017]

MAPK10 links:

MAPK10-AS1 (HGNC:):

MAPK10-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MAPK10. . Gene score misZ 3.0399 (greater than the threshold 3.09). Trascript score misZ 3.6358 (greater than threshold 3.09). GenCC has associacion of gene with Lennox-Gastaut syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.10863942).

BS2

High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPK10	NM_138982.4 linkuse as main transcript	c.121A>C	p.Lys41Gln	missense_variant	4/14	ENST00000641462.2	NP_620448.1	P53779-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPK10	ENST00000641462.2 linkuse as main transcript	c.121A>C	p.Lys41Gln	missense_variant	4/14		NM_138982.4	ENSP00000493435.1		P53779-1

Frequencies

GnomAD3 genomes

AF:

0.000257

AC:

AN:

151994

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00230

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:

0.00

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250718

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135508

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000146

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:

0.000327

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1460564

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726600

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000381

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:

0.000199

GnomAD4 genome

AF:

0.000257

AC:

AN:

151994

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00230

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000959

Alfa

AF:

0.0000277

Hom.:

Bravo

AF:

0.000608

ExAC

AF:

0.00000824

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

Jun 22, 2021

The c.121A>C (p.K41Q) alteration is located in exon 4 (coding exon 2) of the MAPK10 gene. This alteration results from a A to C substitution at nucleotide position 121, causing the lysine (K) at amino acid position 41 to be replaced by a glutamine (Q). 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

0.13

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.24

.;.;.;.;.;.;.;T;T;T;T;T;T;T;.;.;.;T;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.;T;.;.;T;.;.;T;T;T;.;.;.;T;.;.;T;.;T;.;T;.;.;T;.;T;T;.;.;.;.;.;.;.;T;.;.;.;.;.;.;T;T;.;.;.;.;.;.;T;T;.;.;.;T;.;T;.;.;.;.;.;.;.;.;.;T;.

Eigen

Benign

-0.048

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;.;.;D;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;D;.;.;D;.;.;.;D;D;.;.;.;D;.;.;.;D;D;D;D;.;.;.;D;D;.;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.;D;.;D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.11

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.55

.;.;.;.;.;.;.;N;N;N;N;N;N;N;.;.;.;N;.;.;.;.;.;.;.;N;.;.;N;.;.;N;.;.;.;.;.;N;.;.;N;.;N;.;.;N;.;N;.;.;.;N;.;.;.;.;.;.;.;.;N;.;.;.;.;.;N;.;N;.;N;.;.;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.36

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;N;N;.;.;.;N;.;N;.;.;.;.;.;.;.;D;.;.;.

REVEL

Benign

0.20

Sift

Benign

0.28

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;T;T;.;.;.;T;.;T;.;.;.;.;.;.;.;D;.;.;.

Sift4G

Benign

0.34

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Polyphen

0.016, 0.0040, 0.039

.;.;.;B;.;.;B;B;B;B;B;B;B;B;.;.;.;B;.;B;B;.;B;B;B;B;.;.;B;B;B;B;B;.;.;B;.;B;B;.;B;.;B;.;.;B;.;B;.;.;.;B;.;.;.;.;B;.;.;B;B;B;.;.;.;.;B;B;B;.;B;B;B;B;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.47, 0.38

MutPred

0.36

Loss of ubiquitination at K41 (P = 0.0218);.;Loss of ubiquitination at K41 (P = 0.0218);.;.;.;.;Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);.;Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);.;.;.;.;.;.;Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);.;Loss of ubiquitination at K41 (P = 0.0218);.;.;Loss of ubiquitination at K41 (P = 0.0218);.;.;Loss of ubiquitination at K41 (P = 0.0218);.;.;Loss of ubiquitination at K41 (P = 0.0218);.;.;Loss of ubiquitination at K41 (P = 0.0218);.;Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);.;Loss of ubiquitination at K41 (P = 0.0218);.;Loss of ubiquitination at K41 (P = 0.0218);.;.;.;Loss of ubiquitination at K41 (P = 0.0218);.;Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);.;.;.;.;.;Loss of ubiquitination at K41 (P = 0.0218);.;.;.;Loss of ubiquitination at K41 (P = 0.0218);.;Loss of ubiquitination at K41 (P = 0.0218);.;Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);.;.;Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);.;Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);.;.;.;.;Loss of ubiquitination at K41 (P = 0.0218);.;.;Loss of ubiquitination at K41 (P = 0.0218);.;Loss of ubiquitination at K41 (P = 0.0218);.;Loss of ubiquitination at K41 (P = 0.0218);.;.;Loss of ubiquitination at K41 (P = 0.0218);.;Loss of ubiquitination at K41 (P = 0.0218);Loss of ubiquitination at K41 (P = 0.0218);

MVP

0.78

MPC

0.15

ClinPred

0.13

GERP RS

5.5

Varity_R

0.24

gMVP

0.47

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