10-48401535-C-A

Variant names:

• chr10-48401535-C-A
• rs3730154
• NM_001323329.2:c.-49-77C>A

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 0.116
• Publications: 4 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 -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 VariationId 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.

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.-49-77C>A		intron	N/A	NP_001310258.1	P45983-1
	MAPK8	NM_001278547.2		c.-49-77C>A		intron	N/A	NP_001265476.1	A1L4K2
	MAPK8	NM_001323322.2		c.-49-77C>A		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.-49-77C>A		intron	N/A	ENSP00000363304.1	P45983-1
	MAPK8	ENST00000374179.8	TSL:1	c.-49-77C>A		intron	N/A	ENSP00000363294.3	P45983-3
	MAPK8	ENST00000395611.7	TSL:2	c.-49-77C>A		intron	N/A	ENSP00000378974.4	P45983-4

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

African (AFR) AF: 0.882 AC: 14230 AN: 16136

American (AMR) AF: 0.990 AC: 23903 AN: 24144

Ashkenazi Jewish (ASJ) AF: 0.939 AC: 16033 AN: 17082

East Asian (EAS) AF: 1.00 AC: 30982 AN: 30984

South Asian (SAS) AF: 0.965 AC: 53567 AN: 55524

European-Finnish (FIN) AF: 1.00 AC: 46484 AN: 46496

Middle Eastern (MID) AF: 0.966 AC: 2931 AN: 3034

European-Non Finnish (NFE) AF: 0.996 AC: 507528 AN: 509696

Other (OTH) AF: 0.984 AC: 34526 AN: 35078

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

African (AFR) AF: 0.888 AC: 36886 AN: 41540

American (AMR) AF: 0.986 AC: 15096 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.948 AC: 3290 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5184 AN: 5186

South Asian (SAS) AF: 0.971 AC: 4682 AN: 4824

European-Finnish (FIN) AF: 1.00 AC: 10618 AN: 10618

Middle Eastern (MID) AF: 0.986 AC: 290 AN: 294

European-Non Finnish (NFE) AF: 0.995 AC: 67687 AN: 68036

Other (OTH) AF: 0.966 AC: 2043 AN: 2114

Alfa AF: 0.982 Hom.: 196519

Bravo AF: 0.959

Asia WGS AF: 0.984 AC: 3419 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.26
PhyloP100		0.12
PromoterAI		-0.030	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3730154; hg19: chr10-49609578;