10-48405106-GATATATAT-GATATATATATAT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001323329.2(MAPK8):​c.252+144_252+147dupATAT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0413 in 234,050 control chromosomes in the GnomAD database, including 150 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.043 (150 hom., cov: 0)
  • Exomes 𝑓: 0.038 (0 hom.)
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 10-48405106-G-GATAT is Benign according to our data. Variant chr10-48405106-G-GATAT is described in ClinVar as Benign. ClinVar VariationId is 1280175.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0648 is higher than 0.05.

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+147dupATAT		intron	N/A	NP_001310258.1	P45983-1
	MAPK8	NM_001278547.2		c.252+144_252+147dupATAT		intron	N/A	NP_001265476.1	A1L4K2
	MAPK8	NM_001323322.2		c.252+144_252+147dupATAT		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+126insATAT		intron	N/A	ENSP00000363304.1	P45983-1
	MAPK8	ENST00000374176.8	TSL:1	c.252+125_252+126insATAT		intron	N/A	ENSP00000363291.4	P45983-4
	MAPK8	ENST00000374179.8	TSL:1	c.252+125_252+126insATAT		intron	N/A	ENSP00000363294.3	P45983-3

Frequencies

GnomAD3 genomes AF: 0.0434 AC: 6260 AN: 144274 Hom.: 150 Cov.: 0

Gnomad AFR AF: 0.0669

Gnomad AMI AF: 0.00351

Gnomad AMR AF: 0.0376

Gnomad ASJ AF: 0.0628

Gnomad EAS AF: 0.0478

Gnomad SAS AF: 0.0443

Gnomad FIN AF: 0.0201

Gnomad MID AF: 0.0405

Gnomad NFE AF: 0.0328

Gnomad OTH AF: 0.0368

GnomAD4 exome AF: 0.0379 AC: 3401 AN: 89714 Hom.: 0 AF XY: 0.0398 AC XY: 1915 AN XY: 48126

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

African (AFR) AF: 0.0243 AC: 67 AN: 2758

American (AMR) AF: 0.0286 AC: 97 AN: 3392

Ashkenazi Jewish (ASJ) AF: 0.0380 AC: 102 AN: 2682

East Asian (EAS) AF: 0.0389 AC: 241 AN: 6192

South Asian (SAS) AF: 0.0124 AC: 35 AN: 2832

European-Finnish (FIN) AF: 0.0302 AC: 273 AN: 9026

Middle Eastern (MID) AF: 0.0440 AC: 17 AN: 386

European-Non Finnish (NFE) AF: 0.0419 AC: 2386 AN: 56972

Other (OTH) AF: 0.0334 AC: 183 AN: 5474

⚠️ 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: 0.0434 AC: 6266 AN: 144336 Hom.: 150 Cov.: 0 AF XY: 0.0435 AC XY: 3048 AN XY: 70108

African (AFR) AF: 0.0669 AC: 2659 AN: 39746

American (AMR) AF: 0.0375 AC: 548 AN: 14608

Ashkenazi Jewish (ASJ) AF: 0.0628 AC: 211 AN: 3360

East Asian (EAS) AF: 0.0476 AC: 237 AN: 4976

South Asian (SAS) AF: 0.0446 AC: 201 AN: 4504

European-Finnish (FIN) AF: 0.0201 AC: 171 AN: 8526

Middle Eastern (MID) AF: 0.0404 AC: 11 AN: 272

European-Non Finnish (NFE) AF: 0.0328 AC: 2151 AN: 65492

Other (OTH) AF: 0.0370 AC: 74 AN: 1998

Alfa AF: 0.0325 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

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;