NM_002745.5:c.*9+295T>G

Variant names:

• chr22-21768900-A-C
• rs2298432
• NM_002745.5:c.*9+295T>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.*9+295T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.693 in 205,208 control chromosomes in the GnomAD database, including 51,389 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 0.72 (40493 hom., cov: 32)
  • Exomes 𝑓: 0.63 (10896 hom.)
• Consequence: MAPK1 NM_002745.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.25
• Publications: 36 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.922 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.*9+295T>G		intron	N/A	NP_002736.3
	MAPK1	NM_138957.3		c.*304T>G		downstream_gene	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.*9+295T>G		intron	N/A	ENSP00000215832.7
	MAPK1	ENST00000491588.1	TSL:2	n.234+295T>G		intron	N/A
	MAPK1	ENST00000398822.7	TSL:1	c.*304T>G		downstream_gene	N/A	ENSP00000381803.3

Frequencies

GnomAD3 genomes AF: 0.715 AC: 108700 AN: 152020 Hom.: 40430 Cov.: 32

Gnomad AFR AF: 0.930

Gnomad AMI AF: 0.607

Gnomad AMR AF: 0.754

Gnomad ASJ AF: 0.679

Gnomad EAS AF: 0.492

Gnomad SAS AF: 0.618

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.623

Gnomad OTH AF: 0.726

GnomAD4 exome AF: 0.631 AC: 33472 AN: 53070 Hom.: 10896 AF XY: 0.630 AC XY: 17243 AN XY: 27386

African (AFR) AF: 0.924 AC: 1659 AN: 1796

American (AMR) AF: 0.756 AC: 1407 AN: 1860

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 1508 AN: 2218

East Asian (EAS) AF: 0.456 AC: 1752 AN: 3840

South Asian (SAS) AF: 0.614 AC: 1502 AN: 2448

European-Finnish (FIN) AF: 0.597 AC: 1003 AN: 1680

Middle Eastern (MID) AF: 0.733 AC: 198 AN: 270

European-Non Finnish (NFE) AF: 0.624 AC: 22109 AN: 35404

Other (OTH) AF: 0.657 AC: 2334 AN: 3554

GnomAD4 genome AF: 0.715 AC: 108824 AN: 152138 Hom.: 40493 Cov.: 32 AF XY: 0.712 AC XY: 52983 AN XY: 74368

African (AFR) AF: 0.930 AC: 38648 AN: 41550

American (AMR) AF: 0.754 AC: 11532 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 2357 AN: 3470

East Asian (EAS) AF: 0.492 AC: 2545 AN: 5174

South Asian (SAS) AF: 0.618 AC: 2978 AN: 4820

European-Finnish (FIN) AF: 0.578 AC: 6103 AN: 10552

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.623 AC: 42362 AN: 67968

Other (OTH) AF: 0.725 AC: 1529 AN: 2108

Alfa AF: 0.650 Hom.: 80042

Bravo AF: 0.737

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.041
DANN	Benign	0.31
PhyloP100		-3.2
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: rs2298432; hg19: chr22-22123189;