22-21772875-C-T

Variant names:

• chr22-21772875-C-T
• rs1057519911
• NM_002745.5:c.964G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP3

The NM_002745.5(MAPK1):​c.964G>A​(p.Glu322Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E322Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAPK1 NM_002745.5 missense, splice_region
• Scores: Splicing: ADA: 0.9647
• Clinical Significance: - - O:1
• Conservation: PhyloP100: 7.86

Genes affected

MAPK1 (HGNC:6871): (mitogen-activated protein kinase 1) This gene encodes a member of the MAP kinase family. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. The activation of this kinase requires its phosphorylation by upstream kinases. Upon activation, this kinase translocates to the nucleus of the stimulated cells, where it phosphorylates nuclear targets. One study also suggests that this protein acts as a transcriptional repressor independent of its kinase activity. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Two alternatively spliced transcript variants encoding the same protein, but differing in the UTRs, have been reported for this gene. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_002745.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-21772875-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 917748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the MAPK1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.6111 (above the threshold of 3.09). Trascript score misZ: 3.6223 (above the threshold of 3.09). GenCC associations: The gene is linked to Noonan syndrome 13.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPK1	NM_002745.5	c.964G>A	p.Glu322Lys	missense_variant, splice_region_variant	Exon 7 of 9	ENST00000215832.11	NP_002736.3
MAPK1	NM_138957.3	c.964G>A	p.Glu322Lys	missense_variant, splice_region_variant	Exon 7 of 8		NP_620407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPK1	ENST00000215832.11	c.964G>A	p.Glu322Lys	missense_variant, splice_region_variant	Exon 7 of 9	1	NM_002745.5	ENSP00000215832.7
MAPK1	ENST00000398822.7	c.964G>A	p.Glu322Lys	missense_variant, splice_region_variant	Exon 7 of 8	1		ENSP00000381803.3
MAPK1	ENST00000544786.1	c.832G>A	p.Glu278Lys	missense_variant, splice_region_variant	Exon 6 of 7	1		ENSP00000440842.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: -

Submissions summary: Other:1

Revision: -

Submissions by phenotype

Neoplasm Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: -

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Pathogenic	4.2	H;H;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.83
MutPred		0.66		Gain of methylation at E322 (P = 0.0025);Gain of methylation at E322 (P = 0.0025);.;
MVP		0.80
MPC		2.8
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.83
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: rs1057519911; hg19: chr22-22127164; COSMIC: COSV53184855; COSMIC: COSV53184855;