rs1062225

Positions:

• chr10-48435183-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001323329.2(MAPK8):​c.*154A>G variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0986 in 559,926 control chromosomes in the GnomAD database, including 3,441 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (771 hom., cov: 32)
  • Exomes 𝑓: 0.10 (2670 hom.)
• Consequence: MAPK8 NM_001323329.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.92

Genes affected

MAPK8 (HGNC:6881): (mitogen-activated protein kinase 8) The protein encoded by this gene is a member of the MAP kinase family. MAP kinases 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. This kinase is activated by various cell stimuli, and targets specific transcription factors, and thus mediates immediate-early gene expression in response to cell stimuli. The activation of this kinase by tumor-necrosis factor alpha (TNF-alpha) is found to be required for TNF-alpha induced apoptosis. This kinase is also involved in UV radiation induced apoptosis, which is thought to be related to cytochrom c-mediated cell death pathway. Studies of the mouse counterpart of this gene suggested that this kinase play a key role in T cell proliferation, apoptosis and differentiation. Several alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Apr 2016]

MAPK8 (HGNC:):

ARHGAP22 (HGNC:30320): (Rho GTPase activating protein 22) This gene encodes a member of the GTPase activating protein family which activates a GTPase belonging to the RAS superfamily of small GTP-binding proteins. The encoded protein is insulin-responsive, is dependent on the kinase Akt and requires the Akt-dependent 14-3-3 binding protein which binds sequentially to two serine residues. The result of these interactions is regulation of cell motility. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 10-48435183-A-G is Benign according to our data. Variant chr10-48435183-A-G is described in ClinVar as [Benign]. Clinvar id is 1276513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPK8	NM_001323329.2	c.*154A>G		3_prime_UTR_variant	12/12	ENST00000374189.6	NP_001310258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPK8	ENST00000374189.6	c.*154A>G		3_prime_UTR_variant	12/12	5	NM_001323329.2	ENSP00000363304.1

Frequencies

GnomAD3 genomes AF: 0.0849 AC: 12915 AN: 152098 Hom.: 772 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.0633

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0336

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.0923

GnomAD4 exome AF: 0.104 AC: 42276 AN: 407710 Hom.: 2670 Cov.: 6 AF XY: 0.102 AC XY: 21337 AN XY: 209738

Gnomad4 AFR exome AF: 0.0212

Gnomad4 AMR exome AF: 0.0585

Gnomad4 ASJ exome AF: 0.113

Gnomad4 EAS exome AF: 0.000224

Gnomad4 SAS exome AF: 0.0316

Gnomad4 FIN exome AF: 0.138

Gnomad4 NFE exome AF: 0.122

Gnomad4 OTH exome AF: 0.0998

GnomAD4 genome AF: 0.0848 AC: 12911 AN: 152216 Hom.: 771 Cov.: 32 AF XY: 0.0847 AC XY: 6300 AN XY: 74414

Gnomad4 AFR AF: 0.0230

Gnomad4 AMR AF: 0.0633

Gnomad4 ASJ AF: 0.121

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0334

Gnomad4 FIN AF: 0.150

Gnomad4 NFE AF: 0.125

Gnomad4 OTH AF: 0.0919

Alfa AF: 0.115 Hom.: 1223

Bravo AF: 0.0776

Asia WGS AF: 0.0150 AC: 51 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs1062225; hg19: chr10-49643226;