22-21772887-C-T

Variant names:

• chr22-21772887-C-T
• rs2068716940
• NM_002745.5:c.952G>A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP2 PP5_Very_Strong

The NM_002745.5(MAPK1):​c.952G>A​(p.Asp318Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D318G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAPK1 NM_002745.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 Pathogenic. Variant got 15 ACMG points.

• PM1: In a short_sequence_motif Cytoplasmic retention motif (size 4) in uniprot entity MK01_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 chr22-21772886-T-C is described in Lovd as [Pathogenic].
• 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.
• PP5: Variant 22-21772887-C-T is Pathogenic according to our data. Variant chr22-21772887-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 917745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-21772887-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPK1	NM_002745.5	c.952G>A	p.Asp318Asn	missense_variant	Exon 7 of 9	ENST00000215832.11	NP_002736.3
MAPK1	NM_138957.3	c.952G>A	p.Asp318Asn	missense_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.952G>A	p.Asp318Asn	missense_variant	Exon 7 of 9	1	NM_002745.5	ENSP00000215832.7
MAPK1	ENST00000398822.7	c.952G>A	p.Asp318Asn	missense_variant	Exon 7 of 8	1		ENSP00000381803.3
MAPK1	ENST00000544786.1	c.820G>A	p.Asp274Asn	missense_variant	Exon 6 of 7	1		ENSP00000440842.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 02, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging gain of function effect (PMID: 32721402); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32721402, 37463579) -

Atypical behavior;C0424503:Abnormal facial shape;C3714756:Intellectual disability;C4025790:Specific learning disability;CN130023:Heart, malformation of Pathogenic:1

Apr 01, 2020

Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Noonan syndrome 13 Pathogenic:1

Nov 09, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	3.2	M;M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.021	D;D;D
Sift4G	Uncertain	0.051	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.68
MutPred		0.59		Loss of phosphorylation at S320 (P = 0.0917);Loss of phosphorylation at S320 (P = 0.0917);.;
MVP		0.80
MPC		1.4
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.77
gMVP		0.77

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: rs2068716940; hg19: chr22-22127176; COSMIC: COSV53184825; COSMIC: COSV53184825;