NM_002745.5:c.609+2319C>T

Variant names:

• chr22-21796693-G-A
• rs7290469
• NM_002745.5:c.609+2319C>T

Variant summary

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

The NM_002745.5(MAPK1):​c.609+2319C>T 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 151,654 control chromosomes in the GnomAD database, including 9,553 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 (9553 hom., cov: 30)
• Consequence: MAPK1 NM_002745.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.76
• Publications: 17 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 = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPK1	NM_002745.5	c.609+2319C>T		intron_variant	Intron 4 of 8	ENST00000215832.11	NP_002736.3
MAPK1	NM_138957.3	c.609+2319C>T		intron_variant	Intron 4 of 7		NP_620407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPK1	ENST00000215832.11	c.609+2319C>T		intron_variant	Intron 4 of 8	1	NM_002745.5	ENSP00000215832.7
MAPK1	ENST00000398822.7	c.609+2319C>T		intron_variant	Intron 4 of 7	1		ENSP00000381803.3
MAPK1	ENST00000544786.1	c.609+2319C>T		intron_variant	Intron 4 of 6	1		ENSP00000440842.1

Frequencies

GnomAD3 genomes AF: 0.343 AC: 51939 AN: 151536 Hom.: 9561 Cov.: 30

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.484

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.404

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

GnomAD4 genome AF: 0.343 AC: 51951 AN: 151654 Hom.: 9553 Cov.: 30 AF XY: 0.337 AC XY: 24992 AN XY: 74140

African (AFR) AF: 0.219 AC: 9049 AN: 41292

American (AMR) AF: 0.367 AC: 5588 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.484 AC: 1677 AN: 3462

East Asian (EAS) AF: 0.209 AC: 1074 AN: 5144

South Asian (SAS) AF: 0.326 AC: 1564 AN: 4798

European-Finnish (FIN) AF: 0.292 AC: 3076 AN: 10536

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.421 AC: 28549 AN: 67876

Other (OTH) AF: 0.402 AC: 846 AN: 2106

Alfa AF: 0.397 Hom.: 38978

Bravo AF: 0.342

Asia WGS AF: 0.254 AC: 884 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.35
DANN	Benign	0.61
PhyloP100		-1.8
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: rs7290469; hg19: chr22-22150982;