10-48405106-GATATATAT-GATATATATATATATATATAT

Variant names:

• chr10-48405106-G-GATATATATATAT
• rs10657070
• NM_001323329.2:c.252+136_252+147dupATATATATATAT

Variant summary

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

The NM_001323329.2(MAPK8):​c.252+136_252+147dupATATATATATAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000234 in 235,294 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000022 (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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 53 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+136_252+147dupATATATATATAT		intron	N/A	NP_001310258.1	P45983-1
	MAPK8	NM_001278547.2		c.252+136_252+147dupATATATATATAT		intron	N/A	NP_001265476.1	A1L4K2
	MAPK8	NM_001323322.2		c.252+136_252+147dupATATATATATAT		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+126insATATATATATAT		intron	N/A	ENSP00000363304.1	P45983-1
	MAPK8	ENST00000374176.8	TSL:1	c.252+125_252+126insATATATATATAT		intron	N/A	ENSP00000363291.4	P45983-4
	MAPK8	ENST00000374179.8	TSL:1	c.252+125_252+126insATATATATATAT		intron	N/A	ENSP00000363294.3	P45983-3

Frequencies

GnomAD3 genomes AF: 0.000360 AC: 52 AN: 144522 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000605

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000205

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000442

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000350

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000220 AC: 2 AN: 90710 Hom.: 0 AF XY: 0.0000411 AC XY: 2 AN XY: 48670

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

African (AFR) AF: 0.00 AC: 0 AN: 2782

American (AMR) AF: 0.00 AC: 0 AN: 3422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2704

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

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9116

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

European-Non Finnish (NFE) AF: 0.0000347 AC: 2 AN: 57644

Other (OTH) AF: 0.00 AC: 0 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: 0.000367 AC: 53 AN: 144584 Hom.: 0 Cov.: 0 AF XY: 0.000327 AC XY: 23 AN XY: 70248

African (AFR) AF: 0.000628 AC: 25 AN: 39788

American (AMR) AF: 0.000205 AC: 3 AN: 14628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 8554

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

European-Non Finnish (NFE) AF: 0.000351 AC: 23 AN: 65620

Other (OTH) AF: 0.00 AC: 0 AN: 2000

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

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;