rs751526420

Variant names:

• chr12-111880505-C-G
• rs751526420
• NM_003668.4:c.638C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-111880505-C-G
• chr12-111880505-C-T

Variant summary

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

The NM_003668.4(MAPKAPK5):​c.638C>G​(p.Pro213Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,566 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P213L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MAPKAPK5 NM_003668.4 missense
• Clinical Significance: Not reported in ClinVar
• 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]

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 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.638C>G	p.Pro213Arg	missense	Exon 8 of 14	NP_003659.2
	MAPKAPK5	NM_001371479.1		c.638C>G	p.Pro213Arg	missense	Exon 8 of 16	NP_001358408.1
	MAPKAPK5	NM_001371480.1		c.638C>G	p.Pro213Arg	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.638C>G	p.Pro213Arg	missense	Exon 8 of 14	ENSP00000449667.2	Q8IW41-2
	MAPKAPK5	ENST00000551404.7	TSL:5	c.638C>G	p.Pro213Arg	missense	Exon 8 of 14	ENSP00000449381.2	Q8IW41-1
	MAPKAPK5	ENST00000549875.1	TSL:5	c.191C>G	p.Pro64Arg	missense	Exon 3 of 9	ENSP00000473467.1	R4GN33

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151960 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461606 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727084

African (AFR) AF: 0.00 AC: 0 AN: 33476

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: 39692

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111806

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151960 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74242

African (AFR) AF: 0.00 AC: 0 AN: 41350

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.90	L
PhyloP100		7.6
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	0.17	N
REVEL	Uncertain	0.31
Sift	Benign	0.35	T
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.58		Loss of glycosylation at P213 (P = 0.035)
MVP		0.85
MPC		0.59
ClinPred		0.68	D
GERP RS		6.0
Varity_R		0.11
gMVP		0.88
Mutation Taster		=38/62	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: rs751526420; hg19: chr12-112318309;