rs397517411

Variant names:

• chr19-4123890-CCGGCGGCGG-C
• rs397517411
• NM_030662.4:c.-24_-16delCCGCCGCCG

Your query was ambiguous. Multiple possible variants found:

• chr19-4123890-CCGGCGGCGG-C
• chr19-4123890-CCGGCGGCGG-CCGGCGG
• chr19-4123890-CCGGCGGCGG-CCGGCGGCGGCGG
• chr19-4123890-CCGGCGGCGG-CCGGCGGCGGCGGCGG
• chr19-4123890-CCGGCGGCGG-CCGGCGGCGGCGGCGGCGG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_030662.4(MAP2K2):​c.-24_-16delCCGCCGCCG variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,404,856 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 8.0e-7 (0 hom.)
• Consequence: MAP2K2 NM_030662.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39
• Publications: 0 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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.-24_-16delCCGCCGCCG		5_prime_UTR	Exon 1 of 11	NP_109587.1	P36507
	MAP2K2	NM_001440688.1		c.-24_-16delCCGCCGCCG		5_prime_UTR	Exon 1 of 9	NP_001427617.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAP2K2	ENST00000262948.10	TSL:1 MANE Select	c.-24_-16delCCGCCGCCG		5_prime_UTR	Exon 1 of 11	ENSP00000262948.4	P36507
	MAP2K2	ENST00000945862.1		c.-24_-16delCCGCCGCCG		5_prime_UTR	Exon 1 of 11	ENSP00000615921.1
	MAP2K2	ENST00000897166.1		c.-24_-16delCCGCCGCCG		5_prime_UTR	Exon 1 of 11	ENSP00000567225.1

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150702 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.000482

GnomAD4 exome AF: 7.97e-7 AC: 1 AN: 1254154 Hom.: 0 AF XY: 0.00000163 AC XY: 1 AN XY: 612716

African (AFR) AF: 0.00 AC: 0 AN: 26182

American (AMR) AF: 0.00 AC: 0 AN: 21552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20804

East Asian (EAS) AF: 0.00 AC: 0 AN: 28090

South Asian (SAS) AF: 0.00 AC: 0 AN: 63408

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3616

European-Non Finnish (NFE) AF: 9.95e-7 AC: 1 AN: 1005150

Other (OTH) AF: 0.00 AC: 0 AN: 51110

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150702 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73532

African (AFR) AF: 0.00 AC: 0 AN: 41268

American (AMR) AF: 0.00 AC: 0 AN: 15130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67482

Other (OTH) AF: 0.000482 AC: 1 AN: 2074

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397517411; hg19: chr19-4123887;