rs375701469

chr19-4101292-C-T

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.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

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 19-4101292-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 GnomAd at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAP2K2	NM_030662.4	c.529-12G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000262948.10
MAP2K2	XM_006722799.3	c.529-12G>A		splice_polypyrimidine_tract_variant, intron_variant
MAP2K2	XM_047439100.1	c.-42-12G>A		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 151934 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000580 AC XY: 57 AN XY: 98308

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.: 0 Cov.: 37 AF XY: 0.000235 AC XY: 165 AN XY: 703484

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: 34 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74314

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.: 0

Bravo AF: 0.000249

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

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	Sep 25, 2023	- -
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	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

Invitae

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

Other links and lift over

dbSNP: rs375701469; hg19: chr19-4101290;