22-21796997-C-G

Variant names:

• chr22-21796997-C-G
• rs5999550
• NM_002745.5:c.609+2015G>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.609+2015G>C 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 151,916 control chromosomes in the GnomAD database, including 22,451 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 (22451 hom., cov: 31)
• Consequence: MAPK1 NM_002745.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.488
• Publications: 7 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPK1	NM_002745.5	c.609+2015G>C		intron_variant	Intron 4 of 8	ENST00000215832.11	NP_002736.3
MAPK1	NM_138957.3	c.609+2015G>C		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+2015G>C		intron_variant	Intron 4 of 8	1	NM_002745.5	ENSP00000215832.7
MAPK1	ENST00000398822.7	c.609+2015G>C		intron_variant	Intron 4 of 7	1		ENSP00000381803.3
MAPK1	ENST00000544786.1	c.609+2015G>C		intron_variant	Intron 4 of 6	1		ENSP00000440842.1

Frequencies

GnomAD3 genomes AF: 0.539 AC: 81887 AN: 151798 Hom.: 22415 Cov.: 31

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.612

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.471

Gnomad FIN AF: 0.364

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.519

Gnomad OTH AF: 0.586

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

GnomAD4 genome AF: 0.540 AC: 81980 AN: 151916 Hom.: 22451 Cov.: 31 AF XY: 0.534 AC XY: 39679 AN XY: 74270

African (AFR) AF: 0.604 AC: 24983 AN: 41396

American (AMR) AF: 0.612 AC: 9344 AN: 15260

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

East Asian (EAS) AF: 0.452 AC: 2333 AN: 5162

South Asian (SAS) AF: 0.471 AC: 2271 AN: 4820

European-Finnish (FIN) AF: 0.364 AC: 3837 AN: 10544

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

European-Non Finnish (NFE) AF: 0.519 AC: 35246 AN: 67950

Other (OTH) AF: 0.582 AC: 1227 AN: 2108

Alfa AF: 0.530 Hom.: 2639

Bravo AF: 0.559

Asia WGS AF: 0.474 AC: 1649 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.1
DANN	Benign	0.33
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs5999550; hg19: chr22-22151286;