22-21790964-T-C

Variant names:

• chr22-21790964-T-C
• rs11704205
• NM_002745.5:c.610-2156A>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.610-2156A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 152,054 control chromosomes in the GnomAD database, including 22,462 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 0.54 (22462 hom., cov: 32)
• Consequence: MAPK1 NM_002745.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.05
• Publications: 8 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.601 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.610-2156A>G		intron	N/A	NP_002736.3
	MAPK1	NM_138957.3		c.610-2156A>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.610-2156A>G		intron	N/A	ENSP00000215832.7	P28482-1
	MAPK1	ENST00000398822.7	TSL:1	c.610-2156A>G		intron	N/A	ENSP00000381803.3	P28482-1
	MAPK1	ENST00000544786.1	TSL:1	c.610-2156A>G		intron	N/A	ENSP00000440842.1	P28482-2

Frequencies

GnomAD3 genomes AF: 0.539 AC: 81944 AN: 151936 Hom.: 22425 Cov.: 32

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.446

Gnomad SAS AF: 0.473

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.587

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

GnomAD4 genome AF: 0.540 AC: 82038 AN: 152054 Hom.: 22462 Cov.: 32 AF XY: 0.534 AC XY: 39699 AN XY: 74310

African (AFR) AF: 0.604 AC: 25026 AN: 41462

American (AMR) AF: 0.612 AC: 9356 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 2128 AN: 3472

East Asian (EAS) AF: 0.446 AC: 2291 AN: 5142

South Asian (SAS) AF: 0.473 AC: 2284 AN: 4824

European-Finnish (FIN) AF: 0.364 AC: 3852 AN: 10576

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.519 AC: 35260 AN: 67968

Other (OTH) AF: 0.583 AC: 1232 AN: 2114

Alfa AF: 0.385 Hom.: 980

Bravo AF: 0.559

Asia WGS AF: 0.473 AC: 1646 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.3
DANN	Benign	0.32
PhyloP100		-2.0
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: rs11704205; hg19: chr22-22145253;