22-21855846-A-C

Variant names:

• chr22-21855846-A-C
• rs11913721
• NM_002745.5:c.119+11476T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002745.5(MAPK1):​c.119+11476T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 152,124 control chromosomes in the GnomAD database, including 9,608 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.34 (9608 hom., cov: 32)
• Consequence: MAPK1 NM_002745.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.644
• Publications: 11 publications found

Genes affected

MAPK1 (HGNC:6871): (mitogen-activated protein kinase 1) This gene encodes a member of the MAP kinase family. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. The activation of this kinase requires its phosphorylation by upstream kinases. Upon activation, this kinase translocates to the nucleus of the stimulated cells, where it phosphorylates nuclear targets. One study also suggests that this protein acts as a transcriptional repressor independent of its kinase activity. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Two alternatively spliced transcript variants encoding the same protein, but differing in the UTRs, have been reported for this gene. [provided by RefSeq, Jan 2014]

MAPK1 Gene-Disease associations (from GenCC):

• Noonan syndrome 13

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002745.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPK1	NM_002745.5	MANE Select	c.119+11476T>G		intron	N/A	NP_002736.3
	MAPK1	NM_138957.3		c.119+11476T>G		intron	N/A	NP_620407.1	Q1HBJ4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPK1	ENST00000215832.11	TSL:1 MANE Select	c.119+11476T>G		intron	N/A	ENSP00000215832.7	P28482-1
	MAPK1	ENST00000398822.7	TSL:1	c.119+11476T>G		intron	N/A	ENSP00000381803.3	P28482-1
	MAPK1	ENST00000544786.1	TSL:1	c.119+11476T>G		intron	N/A	ENSP00000440842.1	P28482-2

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52113 AN: 152006 Hom.: 9616 Cov.: 32

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.368

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.210

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.405

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.343 AC: 52125 AN: 152124 Hom.: 9608 Cov.: 32 AF XY: 0.337 AC XY: 25060 AN XY: 74368

African (AFR) AF: 0.219 AC: 9081 AN: 41486

American (AMR) AF: 0.367 AC: 5618 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.486 AC: 1685 AN: 3470

East Asian (EAS) AF: 0.210 AC: 1086 AN: 5178

South Asian (SAS) AF: 0.332 AC: 1599 AN: 4816

European-Finnish (FIN) AF: 0.290 AC: 3073 AN: 10580

Middle Eastern (MID) AF: 0.459 AC: 135 AN: 294

European-Non Finnish (NFE) AF: 0.421 AC: 28607 AN: 67996

Other (OTH) AF: 0.403 AC: 849 AN: 2106

Alfa AF: 0.256 Hom.: 653

Bravo AF: 0.343

Asia WGS AF: 0.255 AC: 888 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.8
DANN	Benign	0.54
PhyloP100		0.64
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

Other links and lift over

dbSNP: rs11913721; hg19: chr22-22210135;