10-48405106-GATATATAT-GATATATATATATAT

Variant names:

• chr10-48405106-G-GATATAT
• rs10657070
• NM_001323329.2:c.252+142_252+147dupATATAT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001323329.2(MAPK8):​c.252+142_252+147dupATATAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0534 in 89,736 control chromosomes in the GnomAD database, including 13 homozygotes. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (2318 hom., cov: 0)
  • Exomes 𝑓: 0.053 (13 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAPK8 NM_001323329.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -2 ACMG points.

• BP6: Variant 10-48405106-G-GATATAT is Benign according to our data. Variant chr10-48405106-G-GATATAT is described in ClinVar as Benign. ClinVar VariationId is 1233152.Status of the report is criteria_provided_single_submitter, 1 stars.

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+142_252+147dupATATAT		intron	N/A	NP_001310258.1	P45983-1
	MAPK8	NM_001278547.2		c.252+142_252+147dupATATAT		intron	N/A	NP_001265476.1	A1L4K2
	MAPK8	NM_001323322.2		c.252+142_252+147dupATATAT		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+126insATATAT		intron	N/A	ENSP00000363304.1	P45983-1
	MAPK8	ENST00000374176.8	TSL:1	c.252+125_252+126insATATAT		intron	N/A	ENSP00000363291.4	P45983-4
	MAPK8	ENST00000374179.8	TSL:1	c.252+125_252+126insATATAT		intron	N/A	ENSP00000363294.3	P45983-3

Frequencies

GnomAD3 genomes AF: 0.165 AC: 23746 AN: 144164 Hom.: 2318 Cov.: 0

Gnomad AFR AF: 0.0710

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.00981

Gnomad SAS AF: 0.0850

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.185

GnomAD4 exome AF: 0.0534 AC: 4794 AN: 89736 Hom.: 13 AF XY: 0.0581 AC XY: 2796 AN XY: 48136

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

African (AFR) AF: 0.0191 AC: 53 AN: 2768

American (AMR) AF: 0.0359 AC: 122 AN: 3398

Ashkenazi Jewish (ASJ) AF: 0.0583 AC: 156 AN: 2676

East Asian (EAS) AF: 0.00176 AC: 11 AN: 6256

South Asian (SAS) AF: 0.00352 AC: 10 AN: 2838

European-Finnish (FIN) AF: 0.0617 AC: 556 AN: 9014

Middle Eastern (MID) AF: 0.0759 AC: 29 AN: 382

European-Non Finnish (NFE) AF: 0.0631 AC: 3591 AN: 56916

Other (OTH) AF: 0.0485 AC: 266 AN: 5488

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.165 AC: 23740 AN: 144224 Hom.: 2318 Cov.: 0 AF XY: 0.160 AC XY: 11212 AN XY: 70050

African (AFR) AF: 0.0710 AC: 2822 AN: 39738

American (AMR) AF: 0.147 AC: 2148 AN: 14596

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 875 AN: 3360

East Asian (EAS) AF: 0.00963 AC: 48 AN: 4986

South Asian (SAS) AF: 0.0853 AC: 384 AN: 4504

European-Finnish (FIN) AF: 0.191 AC: 1617 AN: 8460

Middle Eastern (MID) AF: 0.267 AC: 72 AN: 270

European-Non Finnish (NFE) AF: 0.233 AC: 15271 AN: 65462

Other (OTH) AF: 0.184 AC: 366 AN: 1994

Alfa AF: 0.141 Hom.: 648

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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

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; COSMIC: COSV64408723;