12-111842762-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -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. 15/21 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

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

Verdict is Likely_benign. Variant got -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. gnomad4_exome 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 gnomad4_exome. There are 1 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	c.29C>T	p.Ala10Val	missense_variant	Exon 1 of 14	ENST00000550735.7	NP_003659.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPKAPK5	ENST00000550735.7	c.29C>T	p.Ala10Val	missense_variant	Exon 1 of 14	1	NM_003668.4	ENSP00000449667.2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000584

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000651

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.29C>T (p.A10V) alteration is located in exon 1 (coding exon 1) of the MAPKAPK5 gene. This alteration results from a C to T substitution at nucleotide position 29, causing the alanine (A) at amino acid position 10 to be replaced by a valine (V). 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	0.078
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.12	.;.;T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.69	T;T;T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;N;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.41	N;.;N;.
REVEL	Benign	0.049
Sift	Benign	0.24	T;.;T;.
Sift4G	Benign	0.28	T;.;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.29
MVP		0.60
MPC		0.54
ClinPred		0.24	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.062
gMVP		0.21

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

Other links and lift over

dbSNP: rs2068753853; hg19: chr12-112280566;