19-4090579-G-A

Position:

• chr19-4090579-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030662.4(MAP2K2):​c.*19C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,540,100 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (4 hom.)
• Consequence: MAP2K2 NM_030662.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.519

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-4090579-G-A is Benign according to our data. Variant chr19-4090579-G-A is described in ClinVar as [Benign]. Clinvar id is 138164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4090579-G-A is described in Lovd as [Benign]. Variant chr19-4090579-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0014 (214/152328) while in subpopulation NFE AF= 0.00209 (142/68026). AF 95% confidence interval is 0.00181. There are 1 homozygotes in gnomad4. There are 93 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 214 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K2	NM_030662.4	c.*19C>T		3_prime_UTR_variant	11/11	ENST00000262948.10
MAP2K2	XM_006722799.3	c.*19C>T		3_prime_UTR_variant	9/9
MAP2K2	XM_047439100.1	c.*19C>T		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAP2K2	ENST00000262948.10	c.*19C>T		3_prime_UTR_variant	11/11	1	NM_030662.4	P1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 215 AN: 152210 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00209

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00164 AC: 252 AN: 153956 Hom.: 0 AF XY: 0.00166 AC XY: 135 AN XY: 81520

Gnomad AFR exome AF: 0.000354

Gnomad AMR exome AF: 0.000324

Gnomad ASJ exome AF: 0.00318

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.000843

Gnomad NFE exome AF: 0.00274

Gnomad OTH exome AF: 0.00272

GnomAD4 exome AF: 0.00215 AC: 2981 AN: 1387772 Hom.: 4 Cov.: 30 AF XY: 0.00217 AC XY: 1490 AN XY: 685132

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000504

Gnomad4 ASJ exome AF: 0.00291

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.000892

Gnomad4 NFE exome AF: 0.00244

Gnomad4 OTH exome AF: 0.00195

GnomAD4 genome AF: 0.00140 AC: 214 AN: 152328 Hom.: 1 Cov.: 33 AF XY: 0.00125 AC XY: 93 AN XY: 74500

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000470

Gnomad4 NFE AF: 0.00209

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00161 Hom.: 0

Bravo AF: 0.00146

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 25, 2019	Variant summary: MAP2K2 c.*19C>T is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.0016 in 153956 control chromosomes (gnomAD). The observed variant frequency is approximately 655 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. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 01, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.1
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs145743390; hg19: chr19-4090577;