NM_002745.5:c.857-1944T>C

Variant names:

• chr22-21774926-A-G
• rs743409
• NM_002745.5:c.857-1944T>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.857-1944T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 151,856 control chromosomes in the GnomAD database, including 23,147 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 0.55 (23147 hom., cov: 30)
• Consequence: MAPK1 NM_002745.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.213
• Publications: 23 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.641 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPK1	NM_002745.5	c.857-1944T>C		intron_variant	Intron 6 of 8	ENST00000215832.11	NP_002736.3
MAPK1	NM_138957.3	c.857-1944T>C		intron_variant	Intron 6 of 7		NP_620407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPK1	ENST00000215832.11	c.857-1944T>C		intron_variant	Intron 6 of 8	1	NM_002745.5	ENSP00000215832.7
MAPK1	ENST00000398822.7	c.857-1944T>C		intron_variant	Intron 6 of 7	1		ENSP00000381803.3
MAPK1	ENST00000544786.1	c.725-1944T>C		intron_variant	Intron 5 of 6	1		ENSP00000440842.1

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83101 AN: 151738 Hom.: 23108 Cov.: 30

Gnomad AFR AF: 0.604

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.651

Gnomad ASJ AF: 0.617

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.530

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.588

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

GnomAD4 genome AF: 0.548 AC: 83194 AN: 151856 Hom.: 23147 Cov.: 30 AF XY: 0.544 AC XY: 40378 AN XY: 74222

African (AFR) AF: 0.604 AC: 25013 AN: 41398

American (AMR) AF: 0.651 AC: 9929 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 2142 AN: 3472

East Asian (EAS) AF: 0.469 AC: 2422 AN: 5162

South Asian (SAS) AF: 0.530 AC: 2556 AN: 4822

European-Finnish (FIN) AF: 0.368 AC: 3870 AN: 10520

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.521 AC: 35419 AN: 67922

Other (OTH) AF: 0.583 AC: 1231 AN: 2110

Alfa AF: 0.530 Hom.: 10713

Bravo AF: 0.569

Asia WGS AF: 0.517 AC: 1798 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.9
DANN	Benign	0.69
PhyloP100		0.21
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: rs743409; hg19: chr22-22129215;