1-206732596-G-T

Position:

• chr1-206732596-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_032960.4(MAPKAPK2):​c.1081G>T​(p.Ala361Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,613,974 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (19 hom.)
• Consequence: MAPKAPK2 NM_032960.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 10.0

Genes affected

MAPKAPK2 (HGNC:6887): (MAPK activated protein kinase 2) This gene encodes a member of the Ser/Thr protein kinase family. This kinase is regulated through direct phosphorylation by p38 MAP kinase. In conjunction with p38 MAP kinase, this kinase is known to be involved in many cellular processes including stress and inflammatory responses, nuclear export, gene expression regulation and cell proliferation. Heat shock protein HSP27 was shown to be one of the substrates of this kinase in vivo. Two transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011110544).
• BP6: Variant 1-206732596-G-T is Benign according to our data. Variant chr1-206732596-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 2639864.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00143 (2089/1461748) while in subpopulation MID AF= 0.0252 (143/5670). AF 95% confidence interval is 0.0219. There are 19 homozygotes in gnomad4_exome. There are 1144 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 248 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPKAPK2	NM_032960.4	c.1081G>T	p.Ala361Ser	missense_variant	10/10	ENST00000367103.4	NP_116584.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPKAPK2	ENST00000367103.4	c.1081G>T	p.Ala361Ser	missense_variant	10/10	1	NM_032960.4	ENSP00000356070	P1
MAPKAPK2	ENST00000294981.8	c.*505G>T		3_prime_UTR_variant	10/10	1		ENSP00000294981

Frequencies

GnomAD3 genomes AF: 0.00163 AC: 248 AN: 152108 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00225 AC: 566 AN: 251460 Hom.: 4 AF XY: 0.00256 AC XY: 348 AN XY: 135906

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.00963

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00258

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00230

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00143 AC: 2089 AN: 1461748 Hom.: 19 Cov.: 32 AF XY: 0.00157 AC XY: 1144 AN XY: 727178

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00313

Gnomad4 ASJ exome AF: 0.00922

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00276

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00101

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.00163 AC: 248 AN: 152226 Hom.: 2 Cov.: 32 AF XY: 0.00171 AC XY: 127 AN XY: 74422

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00176

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00245 Hom.: 6

Bravo AF: 0.00167

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00208 AC: 253

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00539

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

MAPKAPK2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.23
Sift	Benign	0.073	T
Sift4G	Uncertain	0.030	D
Polyphen		0.10	B
Vest4		0.66
MVP		0.69
MPC		1.3
ClinPred		0.081	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs55894011; hg19: chr1-206905941; COSMIC: COSV54315596; COSMIC: COSV54315596;