22-21782109-T-G

Variant names:

• chr22-21782109-T-G
• rs9607272
• NM_002745.5:c.856+6148A>C

Variant summary

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

The NM_002745.5(MAPK1):​c.856+6148A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.184 in 151,902 control chromosomes in the GnomAD database, including 2,878 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 0.18 (2878 hom., cov: 32)
• Consequence: MAPK1 NM_002745.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.106
• Publications: 18 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: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.231 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPK1	NM_002745.5	MANE Select	c.856+6148A>C		intron	N/A	NP_002736.3
	MAPK1	NM_138957.3		c.856+6148A>C		intron	N/A	NP_620407.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPK1	ENST00000215832.11	TSL:1 MANE Select	c.856+6148A>C		intron	N/A	ENSP00000215832.7
	MAPK1	ENST00000398822.7	TSL:1	c.856+6148A>C		intron	N/A	ENSP00000381803.3
	MAPK1	ENST00000544786.1	TSL:1	c.724+6585A>C		intron	N/A	ENSP00000440842.1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27957 AN: 151784 Hom.: 2874 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.230

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.263

Gnomad EAS AF: 0.0995

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.211

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

GnomAD4 genome AF: 0.184 AC: 27962 AN: 151902 Hom.: 2878 Cov.: 32 AF XY: 0.181 AC XY: 13412 AN XY: 74218

African (AFR) AF: 0.112 AC: 4631 AN: 41444

American (AMR) AF: 0.191 AC: 2909 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 910 AN: 3466

East Asian (EAS) AF: 0.0997 AC: 514 AN: 5154

South Asian (SAS) AF: 0.100 AC: 483 AN: 4812

European-Finnish (FIN) AF: 0.178 AC: 1878 AN: 10536

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15919 AN: 67938

Other (OTH) AF: 0.209 AC: 440 AN: 2106

Alfa AF: 0.212 Hom.: 4653

Bravo AF: 0.180

Asia WGS AF: 0.105 AC: 365 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.5
DANN	Benign	0.53
PhyloP100		0.11
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: rs9607272; hg19: chr22-22136398;