12-111880495-C-A

Variant names:

• chr12-111880495-C-A
• rs2070158266
• NM_003668.4:c.628C>A

Variant summary

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

The NM_003668.4(MAPKAPK5):​c.628C>A​(p.Pro210Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MAPKAPK5 NM_003668.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• 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]

RPS2P41 (HGNC:36357): (ribosomal protein S2 pseudogene 41)

ACMG classification

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_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.628C>A	p.Pro210Thr	missense	Exon 8 of 14	NP_003659.2
	MAPKAPK5	NM_001371479.1		c.628C>A	p.Pro210Thr	missense	Exon 8 of 16	NP_001358408.1
	MAPKAPK5	NM_001371480.1		c.628C>A	p.Pro210Thr	missense	Exon 8 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.628C>A	p.Pro210Thr	missense	Exon 8 of 14	ENSP00000449667.2	Q8IW41-2
	MAPKAPK5	ENST00000551404.7	TSL:5	c.628C>A	p.Pro210Thr	missense	Exon 8 of 14	ENSP00000449381.2	Q8IW41-1
	MAPKAPK5	ENST00000549875.1	TSL:5	c.181C>A	p.Pro61Thr	missense	Exon 3 of 9	ENSP00000473467.1	R4GN33

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461652 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727100

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111838

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.36
Sift	Benign	0.065	T
Sift4G	Benign	0.32	T
Polyphen		1.0	D
Vest4		0.65
MutPred		0.46		Gain of glycosylation at P210 (P = 0.0181)
MVP		0.84
MPC		0.62
ClinPred		0.67	D
GERP RS		6.0
Varity_R		0.16
gMVP		0.82
Mutation Taster		=39/61	disease causing

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: rs2070158266; hg19: chr12-112318299;