Genetic Variant MAPK8:c.252+142_252+147delATATAT (chr10-48405106-GATATAT-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The NM_001323329.2(MAPK8):c.252+142_252+147delATATAT 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 235,154 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000062 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00051 ( 0 hom. )

Consequence

MAPK8
NM_001323329.2 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.751

Publications

1 publications found

Variant links:

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]

MAPK8 links:

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ACMG classification

Classification was made for transcript

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

BS2

High AC in GnomAd4 at 9 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MAPK8	NM_001323329.2	MANE Select	c.252+142_252+147delATATAT	intron	N/A	NP_001310258.1	P45983-1
MAPK8	NM_001278547.2		c.252+142_252+147delATATAT	intron	N/A	NP_001265476.1	A1L4K2
MAPK8	NM_001323322.2		c.252+142_252+147delATATAT	intron	N/A	NP_001310251.1	P45983-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MAPK8	ENST00000374189.6	TSL:5 MANE Select	c.252+126_252+131delATATAT	intron	N/A	ENSP00000363304.1	P45983-1
MAPK8	ENST00000374176.8	TSL:1	c.252+126_252+131delATATAT	intron	N/A	ENSP00000363291.4	P45983-4
MAPK8	ENST00000374179.8	TSL:1	c.252+126_252+131delATATAT	intron	N/A	ENSP00000363294.3	P45983-3

Frequencies

GnomAD3 genomes

AF:

0.0000623

AC:

AN:

144522

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000305

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000508

AC:

AN:

90632

Hom.:

AF XY:

0.000350

AC XY:

AN XY:

48628

show subpopulations

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

African (AFR)

AF:

0.00180

AC:

AN:

2782

American (AMR)

AF:

0.000585

AC:

AN:

3416

Ashkenazi Jewish (ASJ)

AF:

0.000370

AC:

AN:

2700

East Asian (EAS)

AF:

0.000319

AC:

AN:

6266

South Asian (SAS)

AF:

0.00

AC:

AN:

2840

European-Finnish (FIN)

AF:

0.000439

AC:

AN:

9112

Middle Eastern (MID)

AF:

0.00

AC:

AN:

390

European-Non Finnish (NFE)

AF:

0.000486

AC:

AN:

57590

Other (OTH)

AF:

0.000723

AC:

AN:

5536

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.297

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000623

AC:

AN:

144522

Hom.:

Cov.:

AF XY:

0.0000428

AC XY:

AN XY:

70170

show subpopulations

African (AFR)

AF:

0.000176

AC:

AN:

39700

American (AMR)

AF:

0.00

AC:

AN:

14612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3364

East Asian (EAS)

AF:

0.00

AC:

AN:

4998

South Asian (SAS)

AF:

0.00

AC:

AN:

4526

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

296

European-Non Finnish (NFE)

AF:

0.0000305

AC:

AN:

65632

Other (OTH)

AF:

0.00

AC:

AN:

1986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.586

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

648

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.75

Splicing

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

Publications

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10-48405106-GATATATAT-GAT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over