19-4101151-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_030662.4(MAP2K2):c.581-8G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,510,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: MAP2K2 NM_030662.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0005268
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.72

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-4101151-C-T is Benign according to our data. Variant chr19-4101151-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 227539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K2	NM_030662.4	c.581-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000262948.10
MAP2K2	XM_006722799.3	c.581-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
MAP2K2	XM_047439100.1	c.11-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K2	ENST00000262948.10	c.581-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_030662.4	P1

Frequencies

GnomAD3 genomes AF: 0.000115 AC: 17 AN: 147398 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000649

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000897

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000809 AC: 19 AN: 234782 Hom.: 0 AF XY: 0.0000629 AC XY: 8 AN XY: 127236

Gnomad AFR exome AF: 0.000344

Gnomad AMR exome AF: 0.0000602

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000344

Gnomad SAS exome AF: 0.0000349

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000381

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.000101 AC: 137 AN: 1363054 Hom.: 0 Cov.: 56 AF XY: 0.000106 AC XY: 72 AN XY: 676882

Gnomad4 AFR exome AF: 0.000132

Gnomad4 AMR exome AF: 0.0000488

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000250

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000110

Gnomad4 OTH exome AF: 0.000112

GnomAD4 genome AF: 0.000115 AC: 17 AN: 147530 Hom.: 0 Cov.: 32 AF XY: 0.0000973 AC XY: 7 AN XY: 71944

Gnomad4 AFR AF: 0.000198

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000650

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000897

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000159

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 25, 2015	c.581-8G>A in intron 5 of MAP2K2: This variant is not expected to have clinical significance because a change at this position does not diverge from the splice consensus sequence and is therefore unlikely to impact splicing. Furthermore, sp lice variants are not a known mechanism of disease for Noonan syndrome. It has b een identified in 5/67874 ethnically diverse chromosomes by the Exome Aggregatio n Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs369262004). -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 01, 2020	Variant summary: MAP2K2 c.581-8G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.1e-05 in 234782 control chromosomes. The observed variant frequency is approximately 32 fold of the estimated maximal expected allele frequency for a pathogenic variant in MAP2K2 causing Noonan Syndrome And Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. c.581-8G>A has been reported in the literature in individuals affected with Noonan Syndrome And Related Conditions (example, Justino_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome And Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 03, 2021

- -

Cardiofaciocutaneous syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 26, 2023

- -

RASopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.3
Dann	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00053
dbscSNV1_RF	Benign	0.036
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

Publications

LitVar

Other links and lift over

dbSNP: rs369262004; hg19: chr19-4101149;