22-21832804-G-T

Variant names:

• chr22-21832804-G-T
• rs9610375
• NM_002745.5:c.120-24958C>A

Variant summary

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

The NM_002745.5(MAPK1):​c.120-24958C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 151,626 control chromosomes in the GnomAD database, including 12,938 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 0.40 (12938 hom., cov: 29)
• Consequence: MAPK1 NM_002745.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.156
• Publications: 22 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)

ENSG00000289564 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.469 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.120-24958C>A		intron	N/A	NP_002736.3
	MAPK1	NM_138957.3		c.120-24958C>A		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.120-24958C>A		intron	N/A	ENSP00000215832.7	P28482-1
	MAPK1	ENST00000398822.7	TSL:1	c.120-24958C>A		intron	N/A	ENSP00000381803.3	P28482-1
	MAPK1	ENST00000544786.1	TSL:1	c.120-24958C>A		intron	N/A	ENSP00000440842.1	P28482-2

Frequencies

GnomAD3 genomes AF: 0.405 AC: 61293 AN: 151506 Hom.: 12934 Cov.: 29

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.428

Gnomad AMR AF: 0.434

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.476

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

GnomAD4 genome AF: 0.405 AC: 61336 AN: 151626 Hom.: 12938 Cov.: 29 AF XY: 0.397 AC XY: 29400 AN XY: 74058

African (AFR) AF: 0.309 AC: 12800 AN: 41384

American (AMR) AF: 0.434 AC: 6619 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 2041 AN: 3466

East Asian (EAS) AF: 0.230 AC: 1169 AN: 5074

South Asian (SAS) AF: 0.354 AC: 1697 AN: 4796

European-Finnish (FIN) AF: 0.317 AC: 3336 AN: 10514

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.473 AC: 32125 AN: 67856

Other (OTH) AF: 0.473 AC: 994 AN: 2102

Alfa AF: 0.453 Hom.: 43561

Bravo AF: 0.409

Asia WGS AF: 0.290 AC: 1009 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.8
DANN	Benign	0.70
PhyloP100		-0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9610375; hg19: chr22-22187093;