chr22-21760715-C-G

Variant names:

• chr22-21760715-C-G
• rs6928
• NM_002745.5:c.*3535G>C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPK1	NM_002745.5	c.*3535G>C		3_prime_UTR_variant	Exon 9 of 9	ENST00000215832.11	NP_002736.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPK1	ENST00000215832	c.*3535G>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_002745.5	ENSP00000215832.7

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

Gnomad4 OTH exome AF: 0.500

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

Gnomad4 AFR AF: 0.443

Gnomad4 AMR AF: 0.589

Gnomad4 ASJ AF: 0.613

Gnomad4 EAS AF: 0.447

Gnomad4 SAS AF: 0.470

Gnomad4 FIN AF: 0.358

Gnomad4 NFE AF: 0.518

Gnomad4 OTH AF: 0.548

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs6928; hg19: chr22-22115004;