chr12-111842762-C-T

Variant names:

• chr12-111842762-C-T
• rs2068753853
• NM_003668.4:c.29C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_003668.4(MAPKAPK5):​c.29C>T​(p.Ala10Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000253 in 1,187,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: MAPKAPK5 NM_003668.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.85
• 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-AS1 (HGNC:24091): (MAPKAPK5 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12233508).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00000253 (3/1187618) while in subpopulation EAS AF = 0.0000651 (2/30704). AF 95% confidence interval is 0.0000108. There are 0 homozygotes in GnomAdExome4. There are 1 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.29C>T	p.Ala10Val	missense	Exon 1 of 14	NP_003659.2
	MAPKAPK5	NM_001371479.1		c.29C>T	p.Ala10Val	missense	Exon 1 of 16	NP_001358408.1
	MAPKAPK5	NM_001371480.1		c.29C>T	p.Ala10Val	missense	Exon 1 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.29C>T	p.Ala10Val	missense	Exon 1 of 14	ENSP00000449667.2	Q8IW41-2
	MAPKAPK5-AS1	ENST00000428207.5	TSL:1	n.141G>A		non_coding_transcript_exon	Exon 1 of 2
	MAPKAPK5-AS1	ENST00000456429.7	TSL:1	n.141G>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000253 AC: 3 AN: 1187618 Hom.: 0 Cov.: 30 AF XY: 0.00000174 AC XY: 1 AN XY: 573546

African (AFR) AF: 0.00 AC: 0 AN: 25102

American (AMR) AF: 0.0000584 AC: 1 AN: 17126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15884

East Asian (EAS) AF: 0.0000651 AC: 2 AN: 30704

South Asian (SAS) AF: 0.00 AC: 0 AN: 34234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4704

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 969780

Other (OTH) AF: 0.00 AC: 0 AN: 47340

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

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	0.078
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.049
Sift	Benign	0.24	T
Sift4G	Benign	0.28	T
Polyphen		0.0	B
Vest4		0.29
MVP		0.60
MPC		0.54
ClinPred		0.24	T
GERP RS		3.2
PromoterAI		-0.064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.062
gMVP		0.21
Mutation Taster		=87/13	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: rs2068753853; hg19: chr12-112280566;