rs350911

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.919+12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.731 in 1,590,206 control chromosomes in the GnomAD database, including 427,013 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.75 ( 42595 hom., cov: 33)

Exomes 𝑓: 0.73 ( 384418 hom. )

Consequence

MAP2K2
NM_030662.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: -0.898

Publications

22 publications found

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]

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=-0.88).

BP6

Variant 19-4099189-T-C is Benign according to our data. Variant chr19-4099189-T-C is described in ClinVar as Benign. ClinVar VariationId is 40835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.912 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4 link	c.919+12A>G	intron_variant	Intron 7 of 10	ENST00000262948.10	NP_109587.1	P36507
MAP2K2	NM_001440688.1 link	c.705+1830A>G	intron_variant	Intron 6 of 8		NP_001427617.1
MAP2K2	NM_001440689.1 link	c.349+12A>G	intron_variant	Intron 5 of 8		NP_001427618.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10 link	c.919+12A>G		intron_variant	Intron 7 of 10	1	NM_030662.4	ENSP00000262948.4		P36507

Frequencies

GnomAD3 genomes

AF:

0.747

AC:

113609

AN:

152032

Hom.:

42566

Cov.:

show subpopulations

Gnomad AFR

AF:

0.744

Gnomad AMI

AF:

0.714

Gnomad AMR

AF:

0.803

Gnomad ASJ

AF:

0.703

Gnomad EAS

AF:

0.934

Gnomad SAS

AF:

0.713

Gnomad FIN

AF:

0.769

Gnomad MID

AF:

0.668

Gnomad NFE

AF:

0.725

Gnomad OTH

AF:

0.728

GnomAD2 exomes

AF:

0.753

AC:

157211

AN:

208772

AF XY:

0.747

show subpopulations

Gnomad AFR exome

AF:

0.738

Gnomad AMR exome

AF:

0.849

Gnomad ASJ exome

AF:

0.714

Gnomad EAS exome

AF:

0.921

Gnomad FIN exome

AF:

0.752

Gnomad NFE exome

AF:

0.713

Gnomad OTH exome

AF:

0.728

GnomAD4 exome

AF:

0.730

AC:

1049346

AN:

1438056

Hom.:

384418

Cov.:

AF XY:

0.729

AC XY:

520249

AN XY:

713878

show subpopulations

African (AFR)

AF:

0.730

AC:

24226

AN:

33170

American (AMR)

AF:

0.841

AC:

35261

AN:

41922

Ashkenazi Jewish (ASJ)

AF:

0.717

AC:

18430

AN:

25708

East Asian (EAS)

AF:

0.935

AC:

36348

AN:

38864

South Asian (SAS)

AF:

0.713

AC:

59797

AN:

83890

European-Finnish (FIN)

AF:

0.754

AC:

36421

AN:

48298

Middle Eastern (MID)

AF:

0.666

AC:

3465

AN:

5204

European-Non Finnish (NFE)

AF:

0.719

AC:

791869

AN:

1101592

Other (OTH)

AF:

0.733

AC:

43529

AN:

59408

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

15428

30857

46285

61714

77142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19878

39756

59634

79512

99390

<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:

0.747

AC:

113687

AN:

152150

Hom.:

42595

Cov.:

AF XY:

0.750

AC XY:

55763

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.744

AC:

30888

AN:

41526

American (AMR)

AF:

0.803

AC:

12282

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.703

AC:

2442

AN:

3472

East Asian (EAS)

AF:

0.934

AC:

4819

AN:

5160

South Asian (SAS)

AF:

0.712

AC:

3441

AN:

4830

European-Finnish (FIN)

AF:

0.769

AC:

8153

AN:

10606

Middle Eastern (MID)

AF:

0.684

AC:

201

AN:

294

European-Non Finnish (NFE)

AF:

0.725

AC:

49274

AN:

67938

Other (OTH)

AF:

0.727

AC:

1536

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1521

3041

4562

6082

7603

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

852

1704

2556

3408

4260

<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:

0.730

Hom.:

8639

Bravo

AF:

0.750

Asia WGS

AF:

0.809

AC:

2811

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

May 09, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 12, 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.919+12A>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 0.75 in 208772 control chromosomes, suggesting that it is the major allele and therefore benign. A ClinVar submission (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Nov 20, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiofaciocutaneous syndrome 4

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

RASopathy

Benign:1

Feb 04, 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

-0.88

CADD

Benign

1.7

(source)

DANN

Benign

0.48

PhyloP100

-0.90

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)

0.020

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