12-111880505-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_003668.4(MAPKAPK5):c.638C>T(p.Pro213Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,566 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

MAPKAPK5
NM_003668.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.57

Variant links:

Genes affected

MAPKAPK5 (HGNC:6889): (MAPK activated protein kinase 5) The protein encoded by this gene is a tumor suppressor and member of the serine/threonine kinase family. In response to cellular stress and proinflammatory cytokines, this kinase is activated through its phosphorylation by MAP kinases including MAPK1/ERK, MAPK14/p38-alpha, and MAPK11/p38-beta. The encoded protein is found in the nucleus but translocates to the cytoplasm upon phosphorylation and activation. This kinase phosphorylates heat shock protein HSP27 at its physiologically relevant sites. Two alternately spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Nov 2012]

MAPKAPK5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000157 (23/1461606) while in subpopulation AFR AF= 0.0000896 (3/33476). AF 95% confidence interval is 0.0000298. There are 0 homozygotes in gnomad4_exome. There are 16 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPKAPK5	NM_003668.4 link	c.638C>T	p.Pro213Leu	missense_variant	Exon 8 of 14	ENST00000550735.7	NP_003659.2	Q8IW41-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAPKAPK5	ENST00000550735.7 link	c.638C>T	p.Pro213Leu	missense_variant	Exon 8 of 14	1	NM_003668.4	ENSP00000449667.2	Q8IW41-2
MAPKAPK5	ENST00000551404.7 link	c.638C>T	p.Pro213Leu	missense_variant	Exon 8 of 14	5		ENSP00000449381.2	Q8IW41-1
MAPKAPK5	ENST00000549875.1 link	c.191C>T	p.Pro64Leu	missense_variant	Exon 3 of 9	5		ENSP00000473467.1	R4GN33
MAPKAPK5	ENST00000553053.5 link	n.191C>T		non_coding_transcript_exon_variant	Exon 3 of 7	5		ENSP00000448408.2	F8VRP2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151960

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00000401

AC:

AN:

249252

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135230

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461606

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151960

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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

Bravo

AF:

0.00000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.638C>T (p.P213L) alteration is located in exon 8 (coding exon 8) of the MAPKAPK5 gene. This alteration results from a C to T substitution at nucleotide position 638, causing the proline (P) at amino acid position 213 to be replaced by a leucine (L). 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

0.30

BayesDel_addAF

Uncertain

0.043

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

.;T;T

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Benign

0.045

MetaRNN

Uncertain

0.54

D;D;D

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.84

L;L;.

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.50

N;N;.

REVEL

Benign

0.26

Sift

Benign

0.13

T;T;.

Sift4G

Uncertain

0.011

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.65

MutPred

0.49

Loss of disorder (P = 0.0087);Loss of disorder (P = 0.0087);.;

MVP

0.80

MPC

0.57

ClinPred

0.72

GERP RS

6.0

Varity_R

0.084

gMVP

0.85

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