Genetic Variant NM_002754.5:c.842C>T (chr6-36138879-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002754.5(MAPK13):c.842C>T(p.Ala281Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,458,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MAPK13
NM_002754.5 missense, splice_region

Scores

Splicing: ADA: 0.9946

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.10

Variant links:

Genes affected

MAPK13 (HGNC:6875): (mitogen-activated protein kinase 13) This gene encodes a member of the mitogen-activated protein (MAP) kinase family. MAP kinases act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. The encoded protein is a p38 MAP kinase and is activated by proinflammatory cytokines and cellular stress. Substrates of the encoded protein include the transcription factor ATF2 and the microtubule dynamics regulator stathmin. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Jul 2012]

MAPK13 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPK13	NM_002754.5 link	c.842C>T	p.Ala281Val	missense_variant, splice_region_variant	Exon 11 of 12	ENST00000211287.9	NP_002745.1	O15264-1A0A024RD04
MAPK13	NR_072996.2 link	n.760C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAPK13	ENST00000211287.9 link	c.842C>T	p.Ala281Val	missense_variant, splice_region_variant	Exon 11 of 12	1	NM_002754.5	ENSP00000211287.4	O15264-1
MAPK13	ENST00000373766.9 link	c.690C>T	p.Gly230Gly	splice_region_variant, synonymous_variant	Exon 9 of 10	1		ENSP00000362871.5	O15264-2
MAPK13	ENST00000373759.1 link	c.*95C>T		3_prime_UTR_variant	Exon 8 of 8	5		ENSP00000362864.1	Q5R3E6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458038

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725176

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

0.0078

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.97

MetaSVM

Benign

-0.31

MutationAssessor

Benign

1.5

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.47

Sift

Uncertain

0.010

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.66

MutPred

0.82

Loss of disorder (P = 0.0686);

MVP

0.89

MPC

0.74

ClinPred

0.98

GERP RS

5.3

Varity_R

0.72

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.79

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over