10-48401535-C-A

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.-49-77C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.985 in 890,478 control chromosomes in the GnomAD database, including 432,140 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70821 hom., cov: 32)
  • Exomes 𝑓: 0.99 (361319 hom.)
• Consequence: MAPK8 NM_001323329.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.116

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=-0.9).
• BP6: Variant 10-48401535-C-A is Benign according to our data. Variant chr10-48401535-C-A is described in ClinVar as [Benign]. Clinvar id is 1223921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPK8	NM_001323329.2	c.-49-77C>A		intron_variant		ENST00000374189.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPK8	ENST00000374189.6	c.-49-77C>A		intron_variant		5	NM_001323329.2	A1

Frequencies

GnomAD3 genomes AF: 0.963 AC: 146583 AN: 152186 Hom.: 70774 Cov.: 32

Gnomad AFR AF: 0.888

Gnomad AMI AF: 0.998

Gnomad AMR AF: 0.986

Gnomad ASJ AF: 0.948

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.970

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.995

Gnomad OTH AF: 0.966

GnomAD4 exome AF: 0.989 AC: 730184 AN: 738174 Hom.: 361319 AF XY: 0.988 AC XY: 381011 AN XY: 385492

Gnomad4 AFR exome AF: 0.882

Gnomad4 AMR exome AF: 0.990

Gnomad4 ASJ exome AF: 0.939

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.965

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.996

Gnomad4 OTH exome AF: 0.984

GnomAD4 genome AF: 0.963 AC: 146686 AN: 152304 Hom.: 70821 Cov.: 32 AF XY: 0.966 AC XY: 71906 AN XY: 74470

Gnomad4 AFR AF: 0.888

Gnomad4 AMR AF: 0.986

Gnomad4 ASJ AF: 0.948

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.971

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.995

Gnomad4 OTH AF: 0.966

Alfa AF: 0.990 Hom.: 109556

Bravo AF: 0.959

Asia WGS AF: 0.984 AC: 3419 AN: 3476

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 69% of patients studied by a panel of primary immunodeficiencies. Number of patients: 66. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	1.4
Dann	Benign	0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3730154; hg19: chr10-49609578;