10-48405106-GATATATAT-GATATATATATATATATAT

Variant names:

• chr10-48405106-G-GATATATATAT
• rs10657070
• NM_001323329.2:c.252+138_252+147dupATATATATAT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001323329.2(MAPK8):​c.252+138_252+147dupATATATATAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00458 in 235,218 control chromosomes in the GnomAD database, including 14 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0072 (14 hom., cov: 0)
  • Exomes 𝑓: 0.00042 (0 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0072 (1040/144534) while in subpopulation AFR AF = 0.0223 (885/39752). AF 95% confidence interval is 0.021. There are 14 homozygotes in GnomAd4. There are 493 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1040 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+138_252+147dupATATATATAT		intron	N/A	NP_001310258.1	P45983-1
	MAPK8	NM_001278547.2		c.252+138_252+147dupATATATATAT		intron	N/A	NP_001265476.1	A1L4K2
	MAPK8	NM_001323322.2		c.252+138_252+147dupATATATATAT		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+125_252+126insATATATATAT		intron	N/A	ENSP00000363304.1	P45983-1
	MAPK8	ENST00000374176.8	TSL:1	c.252+125_252+126insATATATATAT		intron	N/A	ENSP00000363291.4	P45983-4
	MAPK8	ENST00000374179.8	TSL:1	c.252+125_252+126insATATATATAT		intron	N/A	ENSP00000363294.3	P45983-3

Frequencies

GnomAD3 genomes AF: 0.00721 AC: 1041 AN: 144472 Hom.: 14 Cov.: 0

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00390

Gnomad ASJ AF: 0.000595

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00133

Gnomad FIN AF: 0.000468

Gnomad MID AF: 0.00338

Gnomad NFE AF: 0.00114

Gnomad OTH AF: 0.00504

GnomAD4 exome AF: 0.000419 AC: 38 AN: 90684 Hom.: 0 AF XY: 0.000452 AC XY: 22 AN XY: 48654

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

African (AFR) AF: 0.00180 AC: 5 AN: 2776

American (AMR) AF: 0.000584 AC: 2 AN: 3422

Ashkenazi Jewish (ASJ) AF: 0.000370 AC: 1 AN: 2702

East Asian (EAS) AF: 0.00 AC: 0 AN: 6266

South Asian (SAS) AF: 0.00 AC: 0 AN: 2840

European-Finnish (FIN) AF: 0.000768 AC: 7 AN: 9116

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 394

European-Non Finnish (NFE) AF: 0.000260 AC: 15 AN: 57626

Other (OTH) AF: 0.00144 AC: 8 AN: 5542

⚠️ 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: 0.00720 AC: 1040 AN: 144534 Hom.: 14 Cov.: 0 AF XY: 0.00702 AC XY: 493 AN XY: 70216

African (AFR) AF: 0.0223 AC: 885 AN: 39752

American (AMR) AF: 0.00390 AC: 57 AN: 14622

Ashkenazi Jewish (ASJ) AF: 0.000595 AC: 2 AN: 3364

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

South Asian (SAS) AF: 0.00133 AC: 6 AN: 4510

European-Finnish (FIN) AF: 0.000468 AC: 4 AN: 8554

Middle Eastern (MID) AF: 0.00365 AC: 1 AN: 274

European-Non Finnish (NFE) AF: 0.00114 AC: 75 AN: 65612

Other (OTH) AF: 0.00500 AC: 10 AN: 2000

Alfa AF: 0.000734 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

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10657070; hg19: chr10-49613149;