1-206685323-C-G

Variant names:

• chr1-206685323-C-G
• rs782064315
• NM_032960.4:c.94C>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_032960.4(MAPKAPK2):​c.94C>G​(p.Pro32Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,419,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00010 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: MAPKAPK2 NM_032960.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.554

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05351931).
• BS2: High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPKAPK2	NM_032960.4	c.94C>G	p.Pro32Ala	missense_variant	Exon 1 of 10	ENST00000367103.4	NP_116584.2
MAPKAPK2	NM_004759.5	c.94C>G	p.Pro32Ala	missense_variant	Exon 1 of 10		NP_004750.1
MAPKAPK2	XM_005273353.4	c.94C>G	p.Pro32Ala	missense_variant	Exon 1 of 11		XP_005273410.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPKAPK2	ENST00000367103.4	c.94C>G	p.Pro32Ala	missense_variant	Exon 1 of 10	1	NM_032960.4	ENSP00000356070.4
MAPKAPK2	ENST00000294981.8	c.94C>G	p.Pro32Ala	missense_variant	Exon 1 of 10	1		ENSP00000294981.4

Frequencies

GnomAD3 genomes AF: 0.000101 AC: 15 AN: 148336 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000245

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: 0.000107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000195

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000237 AC: 3 AN: 126600 Hom.: 0 AF XY: 0.0000141 AC XY: 1 AN XY: 71158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000578

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000135 AC: 172 AN: 1271368 Hom.: 0 Cov.: 23 AF XY: 0.000117 AC XY: 74 AN XY: 630094

Gnomad4 AFR exome AF: 0.0000791

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000896

Gnomad4 NFE exome AF: 0.000158

Gnomad4 OTH exome AF: 0.000161

GnomAD4 genome AF: 0.000101 AC: 15 AN: 148336 Hom.: 0 Cov.: 30 AF XY: 0.0000968 AC XY: 7 AN XY: 72322

Gnomad4 AFR AF: 0.0000245

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000107

Gnomad4 NFE AF: 0.000195

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000199 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000256 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.94C>G (p.P32A) alteration is located in exon 1 (coding exon 1) of the MAPKAPK2 gene. This alteration results from a C to G substitution at nucleotide position 94, causing the proline (P) at amino acid position 32 to be replaced by an alanine (A). 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	0.054
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Benign	0.84
DEOGEN2	Benign	0.086	.;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.43	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.36	N;N
REVEL	Benign	0.049
Sift	Benign	0.59	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.0050	B;B
Vest4		0.11
MutPred		0.28		Loss of glycosylation at P32 (P = 0.0016);Loss of glycosylation at P32 (P = 0.0016);
MVP		0.58
MPC		0.94
ClinPred		0.028	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.026
gMVP		0.087

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: rs782064315; hg19: chr1-206858668; COSMIC: COSV99685780; COSMIC: COSV99685780;