19-4099254-CCTT-C

Position:

chr19-4099254-CCTT-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_SupportingBP6BS1BS2

The NM_030662.4(MAP2K2):c.863_865del(p.Glu288del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000255 in 1,605,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

MAP2K2
NM_030662.4 inframe_deletion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 5.78

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_030662.4. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 19-4099254-CCTT-C is Benign according to our data. Variant chr19-4099254-CCTT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 503543.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000853 (13/152354) while in subpopulation AMR AF= 0.000653 (10/15310). AF 95% confidence interval is 0.000354. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MAP2K2	NM_030662.4 linkuse as main transcript	c.863_865del	p.Glu288del	inframe_deletion	7/11	ENST00000262948.10	NP_109587.1
MAP2K2	XM_047439100.1 linkuse as main transcript	c.293_295del	p.Glu98del	inframe_deletion	5/9		XP_047295056.1
MAP2K2	XM_006722799.3 linkuse as main transcript	c.705+1762_705+1764del		intron_variant			XP_006722862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10 linkuse as main transcript	c.863_865del	p.Glu288del	inframe_deletion	7/11	1	NM_030662.4	ENSP00000262948	P1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

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:

0.000955

GnomAD3 exomes

AF:

0.0000475

AC:

AN:

231466

Hom.:

AF XY:

0.0000634

AC XY:

AN XY:

126248

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000152

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000344

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000388

Gnomad OTH exome

AF:

0.000176

GnomAD4 exome

AF:

0.0000193

AC:

AN:

1453538

Hom.:

AF XY:

0.0000263

AC XY:

AN XY:

722548

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000137

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.0000235

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.000117

GnomAD4 genome

AF:

0.0000853

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.000653

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:

0.000945

Bravo

AF:

0.000276

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 06, 2018	Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: GnomAd 19:4099252 CCTT / C: Latino 6/32102; well conserved; Not in ClinVar, Pubmed, Google search or HGMD -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 16, 2017	Variant summary: The MAP2K2 c.863_865delAAG (p.Glu288del) variant involves deletion of three adjacent nucleotides. One in silico tool predicts a damaging outcome for this variant. This variant was found in 12/227546 control chromosomes at a frequency of 0.0000527, which is approximately 21 times the estimated maximal expected allele frequency of a pathogenic MAP2K2 variant (0.0000025), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. One internal LCA sample also carried a pathogenic variant in PTPN11 c.172A>G/p.Asn58Asp (scored as DV), further supporting the benign nature of this variant. Taken together, this variant is classified as likely benign. -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 22, 2021	In-frame deletion of 1 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 27060149) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 10, 2022	BP3 -

RASopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 07, 2024

This variant, c.863_865del, results in the deletion of 1 amino acid(s) of the MAP2K2 protein (p.Glu288del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs763469132, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MAP2K2-related conditions. ClinVar contains an entry for this variant (Variation ID: 503543). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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 submitter

clinical testing

Ambry Genetics

Jun 17, 2021

This 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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over