10-48404801-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001323329.2(MAPK8):c.123-51A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0589 in 1,465,298 control chromosomes in the GnomAD database, including 4,635 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.058 (610 hom., cov: 31)
  • Exomes 𝑓: 0.059 (4025 hom.)
• Consequence: MAPK8 NM_001323329.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.735

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 10-48404801-A-C is Benign according to our data. Variant chr10-48404801-A-C is described in ClinVar as [Benign]. Clinvar id is 1223363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPK8	NM_001323329.2	c.123-51A>C		intron_variant		ENST00000374189.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPK8	ENST00000374189.6	c.123-51A>C		intron_variant		5	NM_001323329.2	A1

Frequencies

GnomAD3 genomes AF: 0.0580 AC: 8830 AN: 152132 Hom.: 610 Cov.: 31

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.0652

Gnomad EAS AF: 0.0275

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.0413

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0460

Gnomad OTH AF: 0.0618

GnomAD3 exomes AF: 0.0849 AC: 18235 AN: 214746 Hom.: 1679 AF XY: 0.0821 AC XY: 9598 AN XY: 116888

Gnomad AFR exome AF: 0.0137

Gnomad AMR exome AF: 0.277

Gnomad ASJ exome AF: 0.0696

Gnomad EAS exome AF: 0.0282

Gnomad SAS exome AF: 0.175

Gnomad FIN exome AF: 0.0421

Gnomad NFE exome AF: 0.0446

Gnomad OTH exome AF: 0.0769

GnomAD4 exome AF: 0.0590 AC: 77413 AN: 1313048 Hom.: 4025 Cov.: 18 AF XY: 0.0611 AC XY: 40091 AN XY: 656134

Gnomad4 AFR exome AF: 0.0123

Gnomad4 AMR exome AF: 0.266

Gnomad4 ASJ exome AF: 0.0701

Gnomad4 EAS exome AF: 0.0166

Gnomad4 SAS exome AF: 0.162

Gnomad4 FIN exome AF: 0.0464

Gnomad4 NFE exome AF: 0.0470

Gnomad4 OTH exome AF: 0.0615

GnomAD4 genome AF: 0.0581 AC: 8840 AN: 152250 Hom.: 610 Cov.: 31 AF XY: 0.0631 AC XY: 4699 AN XY: 74448

Gnomad4 AFR AF: 0.0163

Gnomad4 AMR AF: 0.212

Gnomad4 ASJ AF: 0.0652

Gnomad4 EAS AF: 0.0276

Gnomad4 SAS AF: 0.162

Gnomad4 FIN AF: 0.0413

Gnomad4 NFE AF: 0.0460

Gnomad4 OTH AF: 0.0645

Alfa AF: 0.0526 Hom.: 86

Bravo AF: 0.0652

Asia WGS AF: 0.119 AC: 413 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 43% of patients studied by a panel of primary immunodeficiencies. Number of patients: 41. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.59
Dann	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs3730156; hg19: chr10-49612844; COSMIC: COSV64408942;