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GeneBe

19-4090579-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_030662.4(MAP2K2):c.*19C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,540,100 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0021 ( 4 hom. )

Consequence

MAP2K2
NM_030662.4 3_prime_UTR

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.519
Variant links:
Genes affected
MAP2K2 (HGNC:6842): (mitogen-activated protein kinase kinase 2) The protein encoded by this gene is a dual specificity protein kinase that belongs to the MAP kinase kinase family. This kinase is known to play a critical role in mitogen growth factor signal transduction. It phosphorylates and thus activates MAPK1/ERK2 and MAPK2/ERK3. The activation of this kinase itself is dependent on the Ser/Thr phosphorylation by MAP kinase kinase kinases. Mutations in this gene cause cardiofaciocutaneous syndrome (CFC syndrome), a disease characterized by heart defects, cognitive disability, and distinctive facial features similar to those found in Noonan syndrome. The inhibition or degradation of this kinase is also found to be involved in the pathogenesis of Yersinia and anthrax. A pseudogene, which is located on chromosome 7, has been identified for this gene. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
Variant 19-4090579-G-A is Benign according to our data. Variant chr19-4090579-G-A is described in ClinVar as [Benign]. Clinvar id is 138164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4090579-G-A is described in Lovd as [Benign]. Variant chr19-4090579-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0014 (214/152328) while in subpopulation NFE AF= 0.00209 (142/68026). AF 95% confidence interval is 0.00181. There are 1 homozygotes in gnomad4. There are 93 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd at 215 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MAP2K2NM_030662.4 linkuse as main transcriptc.*19C>T 3_prime_UTR_variant 11/11 ENST00000262948.10
MAP2K2XM_006722799.3 linkuse as main transcriptc.*19C>T 3_prime_UTR_variant 9/9
MAP2K2XM_047439100.1 linkuse as main transcriptc.*19C>T 3_prime_UTR_variant 9/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MAP2K2ENST00000262948.10 linkuse as main transcriptc.*19C>T 3_prime_UTR_variant 11/111 NM_030662.4 P1

Frequencies

GnomAD3 genomes
AF:
0.00141
AC:
215
AN:
152210
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000458
Gnomad AMI
AF:
0.0264
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.000470
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00209
Gnomad OTH
AF:
0.00192
GnomAD3 exomes
AF:
0.00164
AC:
252
AN:
153956
Hom.:
0
AF XY:
0.00166
AC XY:
135
AN XY:
81520
show subpopulations
Gnomad AFR exome
AF:
0.000354
Gnomad AMR exome
AF:
0.000324
Gnomad ASJ exome
AF:
0.00318
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00127
Gnomad FIN exome
AF:
0.000843
Gnomad NFE exome
AF:
0.00274
Gnomad OTH exome
AF:
0.00272
GnomAD4 exome
AF:
0.00215
AC:
2981
AN:
1387772
Hom.:
4
Cov.:
30
AF XY:
0.00217
AC XY:
1490
AN XY:
685132
show subpopulations
Gnomad4 AFR exome
AF:
0.000478
Gnomad4 AMR exome
AF:
0.000504
Gnomad4 ASJ exome
AF:
0.00291
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00115
Gnomad4 FIN exome
AF:
0.000892
Gnomad4 NFE exome
AF:
0.00244
Gnomad4 OTH exome
AF:
0.00195
GnomAD4 genome
AF:
0.00140
AC:
214
AN:
152328
Hom.:
1
Cov.:
33
AF XY:
0.00125
AC XY:
93
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.000457
Gnomad4 AMR
AF:
0.000261
Gnomad4 ASJ
AF:
0.00288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00124
Gnomad4 FIN
AF:
0.000470
Gnomad4 NFE
AF:
0.00209
Gnomad4 OTH
AF:
0.00190
Alfa
AF:
0.00161
Hom.:
0
Bravo
AF:
0.00146

ClinVar

Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, criteria provided, single submitterclinical testingGeneDxDec 01, 2011This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 25, 2019Variant summary: MAP2K2 c.*19C>T is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.0016 in 153956 control chromosomes (gnomAD). The observed variant frequency is approximately 655 fold of the estimated maximal expected allele frequency for a pathogenic variant in MAP2K2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -
not provided Benign:1
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.86
Cadd
Benign
5.1
Dann
Benign
0.73
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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: rs145743390; hg19: chr19-4090577; API