22-21769275-A-C

Variant names:

• chr22-21769275-A-C
• NM_002745.5:c.1012T>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_002745.5(MAPK1):​c.1012T>G​(p.Leu338Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAPK1 NM_002745.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.67

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPK1	NM_002745.5	c.1012T>G	p.Leu338Val	missense_variant	Exon 8 of 9	ENST00000215832.11	NP_002736.3
MAPK1	NM_138957.3	c.1012T>G	p.Leu338Val	missense_variant	Exon 8 of 8		NP_620407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPK1	ENST00000215832.11	c.1012T>G	p.Leu338Val	missense_variant	Exon 8 of 9	1	NM_002745.5	ENSP00000215832.7
MAPK1	ENST00000398822.7	c.1012T>G	p.Leu338Val	missense_variant	Exon 8 of 8	1		ENSP00000381803.3
MAPK1	ENST00000544786.1	c.880T>G	p.Leu294Val	missense_variant	Exon 7 of 7	1		ENSP00000440842.1
MAPK1	ENST00000491588.1	n.154T>G		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 03, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;D;.
Eigen	Benign	-0.052
Eigen_PC	Benign	-0.039
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	.;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	2.9	M;M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.0	N;N;N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0060	D;D;D
Sift4G	Benign	0.078	T;T;T
Polyphen		0.16	B;B;.
Vest4		0.60
MutPred		0.37		Loss of stability (P = 0.05);Loss of stability (P = 0.05);.;
MVP		0.84
MPC		1.4
ClinPred		0.90	D
GERP RS		0.99
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-22123564;