rs771613524

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1PP2BP6BS1BS2

The NM_002755.4(MAP2K1):​c.961C>T​(p.Pro321Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,460 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

MAP2K1
NM_002755.4 missense, splice_region

Scores

5
11
3
Splicing: ADA: 0.9947
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 7.62
Variant links:
Genes affected
MAP2K1 (HGNC:6840): (mitogen-activated protein kinase kinase 1) The protein encoded by this gene is a member of the dual specificity protein kinase family, which acts as a mitogen-activated protein (MAP) kinase kinase. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals. This protein kinase lies upstream of MAP kinases and stimulates the enzymatic activity of MAP kinases upon wide variety of extra- and intracellular signals. As an essential component of MAP kinase signal transduction pathway, this kinase is involved in many cellular processes such as proliferation, differentiation, transcription regulation and development. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1
In a domain Protein kinase (size 293) in uniprot entity MP2K1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_002755.4
PP2
Missense variant in the MAP2K1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 35 curated benign missense variants. Gene score misZ: 3.1085 (above the threshold of 3.09). Trascript score misZ: 3.7499 (above the threshold of 3.09). GenCC associations: The gene is linked to Noonan syndrome with multiple lentigines, cardiofaciocutaneous syndrome 1, Noonan syndrome, cardiofaciocutaneous syndrome, cardiofaciocutaneous syndrome 3, Costello syndrome.
BP6
Variant 15-66489215-C-T is Benign according to our data. Variant chr15-66489215-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 582017.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000197 (3/152130) while in subpopulation AMR AF= 0.000196 (3/15278). AF 95% confidence interval is 0.0000529. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAP2K1NM_002755.4 linkc.961C>T p.Pro321Ser missense_variant, splice_region_variant Exon 9 of 11 ENST00000307102.10 NP_002746.1 Q02750-1A4QPA9
MAP2K1NM_001411065.1 linkc.817C>T p.Pro273Ser missense_variant, splice_region_variant Exon 8 of 10 NP_001397994.1
MAP2K1XM_011521783.4 linkc.895C>T p.Pro299Ser missense_variant, splice_region_variant Exon 9 of 11 XP_011520085.1 B4DFY5
MAP2K1XM_017022411.3 linkc.883C>T p.Pro295Ser missense_variant, splice_region_variant Exon 8 of 10 XP_016877900.1 Q02750-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MAP2K1ENST00000307102.10 linkc.961C>T p.Pro321Ser missense_variant, splice_region_variant Exon 9 of 11 1 NM_002755.4 ENSP00000302486.5 Q02750-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152130
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000517
AC:
13
AN:
251482
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000376
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000144
AC:
21
AN:
1461330
Hom.:
0
Cov.:
30
AF XY:
0.00000825
AC XY:
6
AN XY:
726990
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000470
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152130
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxOct 08, 2020Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID #582017; Landrum et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMay 17, 2023- -
Cardiofaciocutaneous syndrome 3;C4551602:Noonan syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
RASopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 21, 2024This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 321 of the MAP2K1 protein (p.Pro321Ser). This variant is present in population databases (rs771613524, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MAP2K1-related conditions. ClinVar contains an entry for this variant (Variation ID: 582017). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MAP2K1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsFeb 10, 2021This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.39
BayesDel_addAF
Benign
-0.036
T
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.45
T;T
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.35
D
MetaRNN
Uncertain
0.59
D;D
MetaSVM
Uncertain
0.52
D
MutationAssessor
Benign
1.4
L;.
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-4.9
D;D
REVEL
Uncertain
0.64
Sift
Uncertain
0.0080
D;D
Sift4G
Uncertain
0.019
D;D
Polyphen
0.49
P;.
Vest4
0.65
MutPred
0.48
Loss of glycosylation at P321 (P = 0.0138);.;
MVP
0.79
MPC
0.71
ClinPred
0.52
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.76
gMVP
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.99
dbscSNV1_RF
Pathogenic
0.93
SpliceAI score (max)
0.010
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: rs771613524; hg19: chr15-66781553; API