chr22-21788739-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_002745.5(MAPK1):ā€‹c.679A>Gā€‹(p.Ile227Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

MAPK1
NM_002745.5 missense

Scores

10
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.90
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a domain Protein kinase (size 288) in uniprot entity MK01_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_002745.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MAPK1. . Gene score misZ 3.6111 (greater than the threshold 3.09). Trascript score misZ 3.6223 (greater than threshold 3.09). GenCC has associacion of gene with Noonan syndrome 13.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MAPK1NM_002745.5 linkuse as main transcriptc.679A>G p.Ile227Val missense_variant 5/9 ENST00000215832.11
MAPK1NM_138957.3 linkuse as main transcriptc.679A>G p.Ile227Val missense_variant 5/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MAPK1ENST00000215832.11 linkuse as main transcriptc.679A>G p.Ile227Val missense_variant 5/91 NM_002745.5 P1P28482-1
MAPK1ENST00000398822.7 linkuse as main transcriptc.679A>G p.Ile227Val missense_variant 5/81 P1P28482-1
MAPK1ENST00000544786.1 linkuse as main transcriptc.679A>G p.Ile227Val missense_variant 5/71 P28482-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461822
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727216
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 15, 2023Variant summary: MAPK1 c.679A>G (p.Ile227Val) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251340 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.679A>G in individuals affected with Noonan Syndrome 13 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Uncertain
0.029
T
BayesDel_noAF
Benign
-0.20
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.25
T;T;.
Eigen
Uncertain
0.36
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.96
.;D;D
M_CAP
Benign
0.012
T
MetaRNN
Uncertain
0.49
T;T;T
MetaSVM
Benign
-0.54
T
MutationAssessor
Benign
0.34
N;N;N
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-0.90
N;N;N
REVEL
Benign
0.19
Sift
Uncertain
0.0020
D;D;D
Sift4G
Uncertain
0.0090
D;D;D
Polyphen
0.59
P;P;.
Vest4
0.48
MutPred
0.56
Loss of catalytic residue at P229 (P = 0.0307);Loss of catalytic residue at P229 (P = 0.0307);Loss of catalytic residue at P229 (P = 0.0307);
MVP
0.75
MPC
1.3
ClinPred
0.73
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.78
gMVP
0.79

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2068913661; hg19: chr22-22143028; API