19-4090574-G-A

Variant names:

• chr19-4090574-G-A
• rs6629
• NM_030662.4:c.*24C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_030662.4(MAP2K2):​c.*24C>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 0.177 in 1,530,080 control chromosomes in the GnomAD database, including 25,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1993 hom., cov: 33)
  • Exomes 𝑓: 0.18 (23302 hom.)
• Consequence: MAP2K2 NM_030662.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.854

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-4090574-G-A is Benign according to our data. Variant chr19-4090574-G-A is described in ClinVar as [Benign]. Clinvar id is 40848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4	c.*24C>T		3_prime_UTR_variant	Exon 11 of 11	ENST00000262948.10	NP_109587.1
MAP2K2	NM_001440688.1	c.*24C>T		3_prime_UTR_variant	Exon 9 of 9
MAP2K2	NM_001440689.1	c.*24C>T		3_prime_UTR_variant	Exon 9 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10	c.*24C>T		3_prime_UTR_variant	Exon 11 of 11	1	NM_030662.4	ENSP00000262948.4

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22270 AN: 152056 Hom.: 1994 Cov.: 33

Gnomad AFR AF: 0.0369

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.138

GnomAD2 exomes AF: 0.182 AC: 27830 AN: 153264 AF XY: 0.183

Gnomad AFR exome AF: 0.0368

Gnomad AMR exome AF: 0.221

Gnomad ASJ exome AF: 0.152

Gnomad EAS exome AF: 0.142

Gnomad FIN exome AF: 0.238

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.181 AC: 249161 AN: 1377906 Hom.: 23302 Cov.: 27 AF XY: 0.181 AC XY: 123236 AN XY: 680786

African (AFR) AF: 0.0311 AC: 970 AN: 31198

American (AMR) AF: 0.214 AC: 7649 AN: 35672

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 3869 AN: 25014

East Asian (EAS) AF: 0.182 AC: 6489 AN: 35642

South Asian (SAS) AF: 0.188 AC: 14773 AN: 78734

European-Finnish (FIN) AF: 0.235 AC: 11320 AN: 48178

Middle Eastern (MID) AF: 0.130 AC: 592 AN: 4568

European-Non Finnish (NFE) AF: 0.183 AC: 193870 AN: 1061664

Other (OTH) AF: 0.168 AC: 9629 AN: 57236

GnomAD4 genome AF: 0.146 AC: 22258 AN: 152174 Hom.: 1993 Cov.: 33 AF XY: 0.150 AC XY: 11189 AN XY: 74398

African (AFR) AF: 0.0369 AC: 1532 AN: 41574

American (AMR) AF: 0.183 AC: 2798 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.159 AC: 553 AN: 3470

East Asian (EAS) AF: 0.153 AC: 790 AN: 5150

South Asian (SAS) AF: 0.189 AC: 913 AN: 4824

European-Finnish (FIN) AF: 0.248 AC: 2626 AN: 10596

Middle Eastern (MID) AF: 0.127 AC: 37 AN: 292

European-Non Finnish (NFE) AF: 0.185 AC: 12590 AN: 67970

Other (OTH) AF: 0.136 AC: 286 AN: 2110

Alfa AF: 0.107 Hom.: 239

Bravo AF: 0.136

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.76
PhyloP100		-0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

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Other links and lift over

dbSNP: rs6629; hg19: chr19-4090572; COSMIC: COSV53567888; COSMIC: COSV53567888;