chr19-4117551-A-C

Position:

• chr19-4117551-A-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5

The ENST00000262948.10(MAP2K2):​c.171T>G​(p.Phe57Leu) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F57C) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAP2K2 ENST00000262948.10 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:4
• Conservation: PhyloP100: 1.38

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 Pathogenic. Variant got 19 ACMG points.

• PS1: Transcript ENST00000262948.10 (MAP2K2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 180911
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in ENST00000262948.10
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-4117552-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 8272.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 19-4117551-A-C is Pathogenic according to our data. Variant chr19-4117551-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376449.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.171T>G	p.Phe57Leu	missense_variant	2/11	ENST00000262948.10	NP_109587.1
MAP2K2	XM_006722799.3	c.171T>G	p.Phe57Leu	missense_variant	2/9		XP_006722862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.171T>G	p.Phe57Leu	missense_variant	2/11	1	NM_030662.4	ENSP00000262948	P1
MAP2K2	ENST00000394867.9	n.610T>G		non_coding_transcript_exon_variant	1/10	5
MAP2K2	ENST00000599345.1	n.368T>G		non_coding_transcript_exon_variant	2/7	5
MAP2K2	ENST00000687128.1	n.610T>G		non_coding_transcript_exon_variant	1/7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461814 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: no assertion criteria provided

Submissions by phenotype

Pancreatic adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Gastric adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant melanoma of skin Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Squamous cell carcinoma of the head and neck Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.81
Sift	Benign	0.081	T
Sift4G	Benign	0.24	T
Polyphen		1.0	D
Vest4		0.85
MutPred		0.81		Loss of catalytic residue at F57 (P = 0.1814);
MVP		0.92
MPC		1.3
ClinPred		0.99	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.50
gMVP		0.74

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

Other links and lift over

dbSNP: rs1057519910; hg19: chr19-4117549; COSMIC: COSV99502205;