12-111866184-C-G

Variant names:

• chr12-111866184-C-G
• rs201672082
• NM_003668.4:c.139C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003668.4(MAPKAPK5):​c.139C>G​(p.Arg47Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R47W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAPKAPK5 NM_003668.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.87
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurocardiofaciodigital syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003668.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPKAPK5	NM_003668.4	MANE Select	c.139C>G	p.Arg47Gly	missense	Exon 3 of 14	NP_003659.2
	MAPKAPK5	NM_001371479.1		c.139C>G	p.Arg47Gly	missense	Exon 3 of 16	NP_001358408.1
	MAPKAPK5	NM_001371480.1		c.139C>G	p.Arg47Gly	missense	Exon 3 of 16	NP_001358409.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPKAPK5	ENST00000550735.7	TSL:1 MANE Select	c.139C>G	p.Arg47Gly	missense	Exon 3 of 14	ENSP00000449667.2	Q8IW41-2
	MAPKAPK5	ENST00000551404.7	TSL:5	c.139C>G	p.Arg47Gly	missense	Exon 3 of 14	ENSP00000449381.2	Q8IW41-1
	MAPKAPK5	ENST00000549875.1	TSL:5	c.37-4901C>G		intron	N/A	ENSP00000473467.1	R4GN33

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.066	T
Polyphen		0.99	D
Vest4		0.91
MutPred		0.63		Loss of MoRF binding (P = 0.0123)
MVP		0.78
MPC		0.79
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.67
gMVP		0.79
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs201672082; hg19: chr12-112303988;