10-48427234-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001323329.2(MAPK8):c.1060+91T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0647 in 857,448 control chromosomes in the GnomAD database, including 3,474 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.062 (624 hom., cov: 32)
  • Exomes 𝑓: 0.065 (2850 hom.)
• Consequence: MAPK8 NM_001323329.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.204

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-48427234-T-G is Benign according to our data. Variant chr10-48427234-T-G is described in ClinVar as [Benign]. Clinvar id is 2688199.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPK8	NM_001323329.2	c.1060+91T>G		intron_variant		ENST00000374189.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPK8	ENST00000374189.6	c.1060+91T>G		intron_variant		5	NM_001323329.2	A1

Frequencies

GnomAD3 genomes AF: 0.0618 AC: 9398 AN: 152178 Hom.: 624 Cov.: 32

Gnomad AFR AF: 0.0295

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.0657

Gnomad EAS AF: 0.0273

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.0415

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0460

Gnomad OTH AF: 0.0636

GnomAD4 exome AF: 0.0653 AC: 46076 AN: 705152 Hom.: 2850 Cov.: 10 AF XY: 0.0683 AC XY: 25277 AN XY: 370036

Gnomad4 AFR exome AF: 0.0283

Gnomad4 AMR exome AF: 0.262

Gnomad4 ASJ exome AF: 0.0702

Gnomad4 EAS exome AF: 0.0156

Gnomad4 SAS exome AF: 0.162

Gnomad4 FIN exome AF: 0.0460

Gnomad4 NFE exome AF: 0.0463

Gnomad4 OTH exome AF: 0.0636

GnomAD4 genome AF: 0.0618 AC: 9414 AN: 152296 Hom.: 624 Cov.: 32 AF XY: 0.0667 AC XY: 4966 AN XY: 74468

Gnomad4 AFR AF: 0.0295

Gnomad4 AMR AF: 0.213

Gnomad4 ASJ AF: 0.0657

Gnomad4 EAS AF: 0.0274

Gnomad4 SAS AF: 0.163

Gnomad4 FIN AF: 0.0415

Gnomad4 NFE AF: 0.0461

Gnomad4 OTH AF: 0.0662

Alfa AF: 0.0278 Hom.: 16

Bravo AF: 0.0693

Asia WGS AF: 0.120 AC: 417 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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 36% of patients studied by a panel of primary immunodeficiencies. Number of patients: 34. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.17
Dann	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs3730161; hg19: chr10-49635277; COSMIC: COSV64410958; COSMIC: COSV64410958;