chr19-4090578-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_030662.4(MAP2K2):c.*20G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,541,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

MAP2K2
NM_030662.4 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0590

Publications

0 publications found

Variant links:

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: Orphanet, ClinGen
cardiofaciocutaneous syndrome 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
neurofibromatosis-Noonan syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Noonan syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

MAP2K2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 19-4090578-C-T is Benign according to our data. Variant chr19-4090578-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 388412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MAP2K2	NM_030662.4 link	c.*20G>A	3_prime_UTR_variant	Exon 11 of 11	ENST00000262948.10	NP_109587.1	P36507
MAP2K2	NM_001440688.1 link	c.*20G>A	3_prime_UTR_variant	Exon 9 of 9		NP_001427617.1
MAP2K2	NM_001440689.1 link	c.*20G>A	3_prime_UTR_variant	Exon 9 of 9		NP_001427618.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10 link	c.*20G>A		3_prime_UTR_variant	Exon 11 of 11	1	NM_030662.4	ENSP00000262948.4		P36507

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000650

AC:

AN:

153782

AF XY:

0.0000860

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000171

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000168

AC:

234

AN:

1389194

Hom.:

Cov.:

AF XY:

0.000159

AC XY:

109

AN XY:

685752

show subpopulations

African (AFR)

AF:

0.0000637

AC:

AN:

31414

American (AMR)

AF:

0.00

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25104

East Asian (EAS)

AF:

0.00

AC:

AN:

35716

South Asian (SAS)

AF:

0.00

AC:

AN:

78986

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48220

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4678

European-Non Finnish (NFE)

AF:

0.000197

AC:

211

AN:

1071798

Other (OTH)

AF:

0.000365

AC:

AN:

57578

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000128

Hom.:

Bravo

AF:

0.000102

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Jul 04, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MAP2K2 c.*20G>A is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 6.5e-05 in 153782 control chromosomes. The observed variant frequency is approximately 87 fold of the estimated maximal expected allele frequency for a pathogenic variant in MAP2K2 causing Cardiofaciocutaneous Syndrome phenotype (7.5e-07), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.*20G>A in individuals affected with Cardiofaciocutaneous Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:1

May 09, 2018

GeneDx

Significance:Likely 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

-0.85

CADD

Benign

4.2

(source)

DANN

Benign

0.70

PhyloP100

0.059

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

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chr19-4090578-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over