NM_030662.4:c.528+46C>A

Variant names:

• chr19-4102330-G-T
• rs377101954
• NM_030662.4:c.528+46C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_030662.4(MAP2K2):​c.528+46C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000748 in 1,336,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: MAP2K2 NM_030662.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.310
• 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, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

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.528+46C>A		intron	N/A	NP_109587.1	P36507
	MAP2K2	NM_001440688.1		c.528+46C>A		intron	N/A	NP_001427617.1
	MAP2K2	NM_001440689.1		c.-43+46C>A		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.528+46C>A		intron	N/A	ENSP00000262948.4	P36507
	MAP2K2	ENST00000945862.1		c.528+46C>A		intron	N/A	ENSP00000615921.1
	MAP2K2	ENST00000897166.1		c.528+46C>A		intron	N/A	ENSP00000567225.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.48e-7 AC: 1 AN: 1336846 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 663856

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31044

American (AMR) AF: 0.00 AC: 0 AN: 36300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24816

East Asian (EAS) AF: 0.00 AC: 0 AN: 36686

South Asian (SAS) AF: 0.00 AC: 0 AN: 78712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5574

European-Non Finnish (NFE) AF: 9.75e-7 AC: 1 AN: 1025696

Other (OTH) AF: 0.00 AC: 0 AN: 56180

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.21
DANN	Benign	0.38
PhyloP100		0.31

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: rs377101954; hg19: chr19-4102328;