19-4101046-G-A

Variant names:

• chr19-4101046-G-A
• rs200874968
• NM_030662.4:c.678C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_030662.4(MAP2K2):​c.678C>T​(p.Ser226Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000411 in 1,575,772 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene MAP2K2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00043 (1 hom.)
• Consequence: MAP2K2 NM_030662.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 1.75
• 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: ClinGen, Orphanet
• cardiofaciocutaneous syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Noonan syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Specifications for MAP2K2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 19-4101046-G-A is Benign according to our data. Variant chr19-4101046-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46240.
• BP7: Synonymous conserved (PhyloP=1.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000269 (41/152268) while in subpopulation NFE AF = 0.00047 (32/68016). AF 95% confidence interval is 0.000342. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 41 AD gene.

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.678C>T	p.Ser226Ser	synonymous	Exon 6 of 11	NP_109587.1	P36507
	MAP2K2	NM_001440688.1		c.678C>T	p.Ser226Ser	synonymous	Exon 6 of 9	NP_001427617.1
	MAP2K2	NM_001440689.1		c.108C>T	p.Ser36Ser	synonymous	Exon 4 of 9	NP_001427618.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K2	ENST00000262948.10	TSL:1 MANE Select	c.678C>T	p.Ser226Ser	synonymous	Exon 6 of 11	ENSP00000262948.4	P36507
	MAP2K2	ENST00000599021.1	TSL:5	c.1C>T	p.Leu1Phe	missense	Exon 1 of 5	ENSP00000471763.1	M0R1B6
	MAP2K2	ENST00000945862.1		c.678C>T	p.Ser226Ser	synonymous	Exon 6 of 11	ENSP00000615921.1

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152150 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000470

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000250 AC: 48 AN: 192220 AF XY: 0.000204

Gnomad AFR exome AF: 0.0000888

Gnomad AMR exome AF: 0.000142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000499

Gnomad OTH exome AF: 0.000394

GnomAD4 exome AF: 0.000426 AC: 606 AN: 1423504 Hom.: 1 Cov.: 30 AF XY: 0.000404 AC XY: 285 AN XY: 704640

African (AFR) AF: 0.00 AC: 0 AN: 32402

American (AMR) AF: 0.000181 AC: 7 AN: 38748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25494

East Asian (EAS) AF: 0.00 AC: 0 AN: 37326

South Asian (SAS) AF: 0.00 AC: 0 AN: 81414

European-Finnish (FIN) AF: 0.0000393 AC: 2 AN: 50872

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5052

European-Non Finnish (NFE) AF: 0.000531 AC: 580 AN: 1093228

Other (OTH) AF: 0.000288 AC: 17 AN: 58968

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152268 Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 16 AN XY: 74464

African (AFR) AF: 0.0000963 AC: 4 AN: 41546

American (AMR) AF: 0.000196 AC: 3 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68016

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000467 Hom.: 0

Bravo AF: 0.000363

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	1	2	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	12
DANN	Benign	0.74
PhyloP100		1.7
PromoterAI		-0.025	Neutral
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs200874968; hg19: chr19-4101044; COSMIC: COSV53568298;