10-48405106-GATATATAT-GATAT

Variant names:

• chr10-48405106-GATAT-G
• rs10657070
• NM_001323329.2:c.252+144_252+147delATAT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001323329.2(MAPK8):​c.252+144_252+147delATAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.004 in 234,726 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0091 (1 hom.)
• Consequence: MAPK8 NM_001323329.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.163
• Publications: 1 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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 120 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001323329.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPK8	NM_001323329.2	MANE Select	c.252+144_252+147delATAT		intron	N/A	NP_001310258.1	P45983-1
	MAPK8	NM_001278547.2		c.252+144_252+147delATAT		intron	N/A	NP_001265476.1	A1L4K2
	MAPK8	NM_001323322.2		c.252+144_252+147delATAT		intron	N/A	NP_001310251.1	P45983-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAPK8	ENST00000374189.6	TSL:5 MANE Select	c.252+126_252+129delATAT		intron	N/A	ENSP00000363304.1	P45983-1
	MAPK8	ENST00000374176.8	TSL:1	c.252+126_252+129delATAT		intron	N/A	ENSP00000363291.4	P45983-4
	MAPK8	ENST00000374179.8	TSL:1	c.252+126_252+129delATAT		intron	N/A	ENSP00000363294.3	P45983-3

Frequencies

GnomAD3 genomes AF: 0.000823 AC: 119 AN: 144516 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00110

Gnomad ASJ AF: 0.00149

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000442

Gnomad FIN AF: 0.000234

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000396

Gnomad OTH AF: 0.00202

GnomAD4 exome AF: 0.00907 AC: 818 AN: 90148 Hom.: 1 AF XY: 0.00823 AC XY: 398 AN XY: 48384

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0199 AC: 54 AN: 2714

American (AMR) AF: 0.0103 AC: 35 AN: 3396

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 29 AN: 2674

East Asian (EAS) AF: 0.00449 AC: 28 AN: 6238

South Asian (SAS) AF: 0.00212 AC: 6 AN: 2826

European-Finnish (FIN) AF: 0.00650 AC: 59 AN: 9076

Middle Eastern (MID) AF: 0.0128 AC: 5 AN: 390

European-Non Finnish (NFE) AF: 0.00940 AC: 539 AN: 57336

Other (OTH) AF: 0.0115 AC: 63 AN: 5498

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000830 AC: 120 AN: 144578 Hom.: 0 Cov.: 0 AF XY: 0.000826 AC XY: 58 AN XY: 70242

African (AFR) AF: 0.00163 AC: 65 AN: 39790

American (AMR) AF: 0.00109 AC: 16 AN: 14626

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 5 AN: 3364

East Asian (EAS) AF: 0.00 AC: 0 AN: 4990

South Asian (SAS) AF: 0.000443 AC: 2 AN: 4510

European-Finnish (FIN) AF: 0.000234 AC: 2 AN: 8552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 274

European-Non Finnish (NFE) AF: 0.000396 AC: 26 AN: 65620

Other (OTH) AF: 0.00200 AC: 4 AN: 1996

Alfa AF: 0.00 Hom.: 648

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism

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: rs10657070; hg19: chr10-49613149;