rs375701469

Positions:

chr19-4101292-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_030662.4(MAP2K2):c.529-12G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,573,860 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 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

MAP2K2
NM_030662.4 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00003217

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0730

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 19-4101292-C-T is Benign according to our data. Variant chr19-4101292-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 138157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000224 (34/152052) while in subpopulation SAS AF= 0.00291 (14/4814). AF 95% confidence interval is 0.00176. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
MAP2K2	NM_030662.4 linkuse as main transcript	c.529-12G>A	splice_polypyrimidine_tract_variant, intron_variant	ENST00000262948.10	NP_109587.1
MAP2K2	XM_006722799.3 linkuse as main transcript	c.529-12G>A	splice_polypyrimidine_tract_variant, intron_variant		XP_006722862.1
MAP2K2	XM_047439100.1 linkuse as main transcript	c.-42-12G>A	splice_polypyrimidine_tract_variant, intron_variant		XP_047295056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAP2K2	ENST00000262948.10 linkuse as main transcript	c.529-12G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_030662.4	ENSP00000262948	P1

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

151934

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00291

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000736

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.000554

AC:

102

AN:

184176

Hom.:

AF XY:

0.000580

AC XY:

AN XY:

98308

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.00138

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000218

Gnomad SAS exome

AF:

0.00210

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000771

Gnomad OTH exome

AF:

0.000616

GnomAD4 exome

AF:

0.000193

AC:

274

AN:

1421808

Hom.:

Cov.:

AF XY:

0.000235

AC XY:

165

AN XY:

703484

show subpopulations

Gnomad4 AFR exome

AF:

0.0000611

Gnomad4 AMR exome

AF:

0.000996

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000159

Gnomad4 SAS exome

AF:

0.00183

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000577

Gnomad4 OTH exome

AF:

0.000272

GnomAD4 genome

AF:

0.000224

AC:

AN:

152052

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00291

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.0000736

Gnomad4 OTH

AF:

0.000476

Alfa

AF:

0.000254

Hom.:

Bravo

AF:

0.000249

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 16, 2015	c.529-12G>A in intron 4 of MAP2K2: This variant is not expected to have clinical significance because it has been identified in 0.2% (16/8642) of South Asian ch romosomes and 0.25% (3/1192) of Latino chromosomes by the Exome Aggregation Cons ortium (ExAC, http://exac.broadinstitute.org; dbSNP rs375701469). This variant i s located in the 3' splice region and computational tools do not suggest an impa ct to splicing. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 25, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 2013	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. -

RASopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

2.3

DANN

Benign

0.60

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000032

dbscSNV1_RF

Benign

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over