NM_030662.4:c.1047-279C>T

Variant names:

• chr19-4094777-G-A
• rs350916
• NM_030662.4:c.1047-279C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_030662.4(MAP2K2):​c.1047-279C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 515,488 control chromosomes in the GnomAD database, including 60,235 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (15847 hom., cov: 33)
  • Exomes 𝑓: 0.49 (44388 hom.)
• Consequence: MAP2K2 NM_030662.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.388
• Publications: 16 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-4094777-G-A is Benign according to our data. Variant chr19-4094777-G-A is described in ClinVar as Benign. ClinVar VariationId is 561820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.1047-279C>T		intron_variant	Intron 9 of 10	ENST00000262948.10	NP_109587.1
MAP2K2	NM_001440688.1	c.768-279C>T		intron_variant	Intron 7 of 8		NP_001427617.1
MAP2K2	NM_001440689.1	c.477-279C>T		intron_variant	Intron 7 of 8		NP_001427618.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.1047-279C>T		intron_variant	Intron 9 of 10	1	NM_030662.4	ENSP00000262948.4

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67881 AN: 151962 Hom.: 15839 Cov.: 33

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.498

Gnomad EAS AF: 0.652

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.471

GnomAD4 exome AF: 0.487 AC: 177030 AN: 363410 Hom.: 44388 Cov.: 1 AF XY: 0.483 AC XY: 91217 AN XY: 189012

African (AFR) AF: 0.293 AC: 3261 AN: 11142

American (AMR) AF: 0.557 AC: 8711 AN: 15640

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 6026 AN: 11724

East Asian (EAS) AF: 0.620 AC: 16149 AN: 26048

South Asian (SAS) AF: 0.410 AC: 15530 AN: 37894

European-Finnish (FIN) AF: 0.487 AC: 10862 AN: 22290

Middle Eastern (MID) AF: 0.461 AC: 729 AN: 1582

European-Non Finnish (NFE) AF: 0.489 AC: 105381 AN: 215554

Other (OTH) AF: 0.482 AC: 10381 AN: 21536

GnomAD4 genome AF: 0.447 AC: 67913 AN: 152078 Hom.: 15847 Cov.: 33 AF XY: 0.447 AC XY: 33207 AN XY: 74356

African (AFR) AF: 0.303 AC: 12570 AN: 41522

American (AMR) AF: 0.545 AC: 8337 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.498 AC: 1726 AN: 3468

East Asian (EAS) AF: 0.652 AC: 3345 AN: 5128

South Asian (SAS) AF: 0.407 AC: 1962 AN: 4824

European-Finnish (FIN) AF: 0.479 AC: 5079 AN: 10598

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.490 AC: 33285 AN: 67934

Other (OTH) AF: 0.470 AC: 991 AN: 2110

Alfa AF: 0.479 Hom.: 25741

Bravo AF: 0.447

Asia WGS AF: 0.493 AC: 1716 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.0
DANN	Benign	0.76
PhyloP100		-0.39
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs350916; hg19: chr19-4094775;