chr10-48434548-A-C

Variant names:

• chr10-48434548-A-C
• rs4838590
• NM_001323329.2:c.1139-336A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001323329.2(MAPK8):​c.1139-336A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 152,022 control chromosomes in the GnomAD database, including 19,910 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 0.50 (19910 hom., cov: 32)
• Consequence: MAPK8 NM_001323329.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.849
• Publications: 4 publications found

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]

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAPK8	NM_001323329.2	c.1139-336A>C		intron_variant	Intron 11 of 11	ENST00000374189.6	NP_001310258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAPK8	ENST00000374189.6	c.1139-336A>C		intron_variant	Intron 11 of 11	5	NM_001323329.2	ENSP00000363304.1

Frequencies

GnomAD3 genomes AF: 0.504 AC: 76580 AN: 151904 Hom.: 19910 Cov.: 32

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.488

Gnomad ASJ AF: 0.588

Gnomad EAS AF: 0.638

Gnomad SAS AF: 0.395

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.539

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

GnomAD4 genome AF: 0.504 AC: 76605 AN: 152022 Hom.: 19910 Cov.: 32 AF XY: 0.504 AC XY: 37433 AN XY: 74328

African (AFR) AF: 0.374 AC: 15498 AN: 41438

American (AMR) AF: 0.488 AC: 7464 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 2039 AN: 3470

East Asian (EAS) AF: 0.639 AC: 3301 AN: 5168

South Asian (SAS) AF: 0.397 AC: 1914 AN: 4818

European-Finnish (FIN) AF: 0.554 AC: 5850 AN: 10562

Middle Eastern (MID) AF: 0.721 AC: 212 AN: 294

European-Non Finnish (NFE) AF: 0.569 AC: 38688 AN: 67962

Other (OTH) AF: 0.533 AC: 1124 AN: 2110

Alfa AF: 0.384 Hom.: 1030

Bravo AF: 0.501

Asia WGS AF: 0.485 AC: 1688 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	12
DANN	Benign	0.85
PhyloP100		0.85
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: rs4838590; hg19: chr10-49642591;