19-4102356-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_030662.4(MAP2K2):c.528+20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00735 in 1,578,872 control chromosomes in the GnomAD database, including 736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.039 ( 401 hom., cov: 33)

Exomes 𝑓: 0.0040 ( 335 hom. )

Consequence

MAP2K2
NM_030662.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.21

Publications

5 publications found

Variant links:

COSMIC-nc: COSV53563340

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]

MAP2K2 Gene-Disease associations (from GenCC):

cardiofaciocutaneous syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
cardiofaciocutaneous syndrome 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
neurofibromatosis-Noonan syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Noonan syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MAP2K2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 19-4102356-T-C is Benign according to our data. Variant chr19-4102356-T-C is described in ClinVar as Benign. ClinVar VariationId is 40804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
MAP2K2	NM_030662.4 link	c.528+20A>G	intron_variant	Intron 4 of 10	ENST00000262948.10	NP_109587.1
MAP2K2	NM_001440688.1 link	c.528+20A>G	intron_variant	Intron 4 of 8		NP_001427617.1
MAP2K2	NM_001440689.1 link	c.-43+20A>G	intron_variant	Intron 2 of 8		NP_001427618.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10 link	c.528+20A>G		intron_variant	Intron 4 of 10	1	NM_030662.4	ENSP00000262948.4

Frequencies

GnomAD3 genomes

AF:

0.0388

AC:

5891

AN:

151742

Hom.:

402

Cov.:

show subpopulations

Gnomad AFR

AF:

0.135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0136

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000624

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000737

Gnomad OTH

AF:

0.0259

GnomAD2 exomes

AF:

0.00949

AC:

1922

AN:

202448

AF XY:

0.00671

show subpopulations

Gnomad AFR exome

AF:

0.136

Gnomad AMR exome

AF:

0.00653

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000657

Gnomad NFE exome

AF:

0.000389

Gnomad OTH exome

AF:

0.00381

GnomAD4 exome

AF:

0.00400

AC:

5709

AN:

1427012

Hom.:

335

Cov.:

AF XY:

0.00337

AC XY:

2382

AN XY:

707532

show subpopulations

African (AFR)

AF:

0.135

AC:

4463

AN:

33038

American (AMR)

AF:

0.00681

AC:

271

AN:

39802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25468

East Asian (EAS)

AF:

0.00

AC:

AN:

38564

South Asian (SAS)

AF:

0.000110

AC:

AN:

82164

European-Finnish (FIN)

AF:

0.0000210

AC:

AN:

47702

Middle Eastern (MID)

AF:

0.00384

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.000378

AC:

414

AN:

1095258

Other (OTH)

AF:

0.00892

AC:

529

AN:

59280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

281

563

844

1126

1407

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

146

292

438

584

730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0388

AC:

5893

AN:

151860

Hom.:

401

Cov.:

AF XY:

0.0376

AC XY:

2791

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.135

AC:

5576

AN:

41418

American (AMR)

AF:

0.0136

AC:

207

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.000195

AC:

AN:

5136

South Asian (SAS)

AF:

0.000624

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000737

AC:

AN:

67880

Other (OTH)

AF:

0.0256

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

256

512

768

1024

1280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0214

Hom.:

Bravo

AF:

0.0439

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Oct 08, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MAP2K2 c.528+20A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0095 in 202448 control chromosomes, predominantly at a frequency of 0.14 within the African or African-American subpopulation in the gnomAD database, including 113 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 56000-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 a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.528+20A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation submitted in 2016) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign.

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

RASopathy

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.98

(source)

DANN

Benign

0.41

PhyloP100

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over