chr19-4090603-C-A

Position:

• chr19-4090603-C-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_030662.4(MAP2K2):​c.1198G>T​(p.Val400Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MAP2K2 NM_030662.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.587

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.108239084).
• BP6: Variant 19-4090603-C-A is Benign according to our data. Variant chr19-4090603-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2548628.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.1198G>T	p.Val400Leu	missense_variant	11/11	ENST00000262948.10	NP_109587.1
MAP2K2	XM_006722799.3	c.919G>T	p.Val307Leu	missense_variant	9/9		XP_006722862.1
MAP2K2	XM_047439100.1	c.628G>T	p.Val210Leu	missense_variant	9/9		XP_047295056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.1198G>T	p.Val400Leu	missense_variant	11/11	1	NM_030662.4	ENSP00000262948	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2023

The c.1198G>T (p.V400L) alteration is located in exon 11 (coding exon 11) of the MAP2K2 gene. This alteration results from a G to T substitution at nucleotide position 1198, causing the valine (V) at amino acid position 400 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiofaciocutaneous syndrome 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

3billion

Sep 20, 2024

The variant was identified in at least one patient who was diagnosed with a different variant in another gene and showed no symptoms related to the gene containing the variant in question. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.75	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	0.85	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.76	N;N
REVEL	Benign	0.12
Sift	Benign	0.11	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.17	B;.
Vest4		0.076
MutPred		0.20		Loss of methylation at R397 (P = 0.1463);.;
MVP		0.58
MPC		0.43
ClinPred		0.36	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-4090601;