22-21760715-C-G

Variant names:

• chr22-21760715-C-G
• rs6928
• NM_002745.5:c.*3535G>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.*3535G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.492 in 151,988 control chromosomes in the GnomAD database, including 18,609 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 0.49 (18609 hom., cov: 32)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: MAPK1 NM_002745.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.25
• Publications: 34 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=-0.72).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.579 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.*3535G>C		3_prime_UTR	Exon 9 of 9	NP_002736.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPK1	ENST00000215832.11	TSL:1 MANE Select	c.*3535G>C		3_prime_UTR	Exon 9 of 9	ENSP00000215832.7
	MAPK1	ENST00000962869.1		c.*3535G>C		3_prime_UTR	Exon 9 of 9	ENSP00000632928.1
	MAPK1	ENST00000879585.1		c.*3557G>C		3_prime_UTR	Exon 9 of 9	ENSP00000549644.1

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74706 AN: 151868 Hom.: 18597 Cov.: 32

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.589

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.552

GnomAD4 exome AF: 0.500 AC: 1 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.492 AC: 74755 AN: 151986 Hom.: 18609 Cov.: 32 AF XY: 0.487 AC XY: 36153 AN XY: 74298

African (AFR) AF: 0.443 AC: 18347 AN: 41442

American (AMR) AF: 0.589 AC: 8996 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 2126 AN: 3470

East Asian (EAS) AF: 0.447 AC: 2308 AN: 5162

South Asian (SAS) AF: 0.470 AC: 2268 AN: 4822

European-Finnish (FIN) AF: 0.358 AC: 3781 AN: 10550

Middle Eastern (MID) AF: 0.623 AC: 182 AN: 292

European-Non Finnish (NFE) AF: 0.518 AC: 35168 AN: 67954

Other (OTH) AF: 0.548 AC: 1156 AN: 2110

Alfa AF: 0.501 Hom.: 2366

Bravo AF: 0.505

Asia WGS AF: 0.458 AC: 1594 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.73
PhyloP100		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs6928; hg19: chr22-22115004;