19-4101223-C-T

Variant names:

• chr19-4101223-C-T
• rs201435249
• NM_030662.4:c.580+6G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.580+6G>A variant in the MAP2K2 gene is 0.311% (91/24374) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) LINK:https://erepo.genome.network/evrepo/ui/classification/CA137955/MONDO:0021060/004

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (5 hom.)
• Consequence: MAP2K2 NM_030662.4 splice_region, intron
• Scores: Splicing: ADA: 0.00003052
• Clinical Significance: Benign reviewed by expert panel B:14
• Conservation: PhyloP100: -0.265
• Publications: 2 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 -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030662.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K2	NM_030662.4	MANE Select	c.580+6G>A		splice_region intron	N/A	NP_109587.1
	MAP2K2	NM_001440688.1		c.580+6G>A		splice_region intron	N/A	NP_001427617.1
	MAP2K2	NM_001440689.1		c.10+6G>A		splice_region intron	N/A	NP_001427618.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K2	ENST00000262948.10	TSL:1 MANE Select	c.580+6G>A		splice_region intron	N/A	ENSP00000262948.4
	MAP2K2	ENST00000945862.1		c.580+6G>A		splice_region intron	N/A	ENSP00000615921.1
	MAP2K2	ENST00000897166.1		c.580+6G>A		splice_region intron	N/A	ENSP00000567225.1

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 264 AN: 151944 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00138 AC: 289 AN: 208960 AF XY: 0.00141

Gnomad AFR exome AF: 0.000803

Gnomad AMR exome AF: 0.000534

Gnomad ASJ exome AF: 0.00372

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000317

Gnomad NFE exome AF: 0.00233

Gnomad OTH exome AF: 0.00189

GnomAD4 exome AF: 0.00282 AC: 4057 AN: 1438420 Hom.: 5 Cov.: 38 AF XY: 0.00268 AC XY: 1909 AN XY: 713262

African (AFR) AF: 0.000544 AC: 18 AN: 33070

American (AMR) AF: 0.000610 AC: 25 AN: 40996

Ashkenazi Jewish (ASJ) AF: 0.00379 AC: 97 AN: 25572

East Asian (EAS) AF: 0.00 AC: 0 AN: 38496

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82574

European-Finnish (FIN) AF: 0.000332 AC: 17 AN: 51192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00343 AC: 3774 AN: 1101318

Other (OTH) AF: 0.00210 AC: 125 AN: 59484

GnomAD4 genome AF: 0.00174 AC: 264 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.00148 AC XY: 110 AN XY: 74338

African (AFR) AF: 0.000651 AC: 27 AN: 41460

American (AMR) AF: 0.000981 AC: 15 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00303 AC: 206 AN: 67956

Other (OTH) AF: 0.00142 AC: 3 AN: 2106

Alfa AF: 0.00246 Hom.: 0

Bravo AF: 0.00183

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	Cardiofaciocutaneous syndrome 4 (2)
-	-	2	not specified (2)
-	-	2	RASopathy (2)
-	-	1	MAP2K2-related disorder (1)
-	-	1	Noonan syndrome and Noonan-related syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.047
DANN	Benign	0.94
PhyloP100		-0.27
PromoterAI		-0.063	Neutral
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
dbscSNV1_RF	Benign	0.0040
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: rs201435249; hg19: chr19-4101221; COSMIC: COSV104543617;