rs193921096

Positions:

• chr4-86017352-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_138982.4(MAPK10):​c.1271G>A​(p.Ser424Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAPK10 NM_138982.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.39

Genes affected

MAPK10 (HGNC:6872): (mitogen-activated protein kinase 10) The protein encoded by this gene is a member of the MAP kinase family. MAP kinases act as integration points for multiple biochemical signals, and thus are involved in a wide variety of cellular processes, such as proliferation, differentiation, transcription regulation and development. This kinase is specifically expressed in a subset of neurons in the nervous system, and is activated by threonine and tyrosine phosphorylation. Targeted deletion of this gene in mice suggests that it may have a role in stress-induced neuronal apoptosis. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. A recent study provided evidence for translational readthrough in this gene, and expression of an additional C-terminally extended isoform via the use of an alternative in-frame translation termination codon. [provided by RefSeq, Dec 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MAPK10. . Gene score misZ 3.0399 (greater than the threshold 3.09). Trascript score misZ 3.6358 (greater than threshold 3.09). GenCC has associacion of gene with Lennox-Gastaut syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15940046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPK10	NM_138982.4	c.1271G>A	p.Ser424Asn	missense_variant	14/14	ENST00000641462.2	NP_620448.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAPK10	ENST00000641462.2	c.1271G>A	p.Ser424Asn	missense_variant	14/14		NM_138982.4	ENSP00000493435	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Benign	0.89
DEOGEN2	Benign	0.37	.;.;.;.;.;.;T;T;T;T;T;T;T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;.;T;.;T;.;.;.;.;.;.;T;.;.;.;.;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	D;D;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;.;D;.;D;.;.;.;D;D;.;.;D;.;D;.;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.4	.;.;.;.;.;.;L;L;L;L;L;L;L;.;L;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;L;.;L;.;.;.;.;.;.;L;.;.;.;.;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PROVEAN	Benign	-0.17	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.31
Sift	Benign	0.61	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.64	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.0020, 0.0030, 0.0010	.;.;.;B;.;B;B;B;B;B;B;B;B;.;B;.;B;B;B;B;B;.;B;B;B;B;B;B;B;.;B;.;B;.;B;B;B;.;.;B;B;.;B;B;B;B
Vest4		0.19, 0.24
MutPred		0.18		Loss of phosphorylation at S424 (P = 0.0118);.;Loss of phosphorylation at S424 (P = 0.0118);.;.;.;Loss of phosphorylation at S424 (P = 0.0118);Loss of phosphorylation at S424 (P = 0.0118);Loss of phosphorylation at S424 (P = 0.0118);Loss of phosphorylation at S424 (P = 0.0118);Loss of phosphorylation at S424 (P = 0.0118);Loss of phosphorylation at S424 (P = 0.0118);Loss of phosphorylation at S424 (P = 0.0118);Loss of phosphorylation at S424 (P = 0.0118);Loss of phosphorylation at S424 (P = 0.0118);Loss of phosphorylation at S424 (P = 0.0118);.;.;.;.;.;.;Loss of phosphorylation at S424 (P = 0.0118);.;.;.;.;.;.;.;Loss of phosphorylation at S424 (P = 0.0118);.;Loss of phosphorylation at S424 (P = 0.0118);.;.;.;.;Loss of phosphorylation at S424 (P = 0.0118);.;Loss of phosphorylation at S424 (P = 0.0118);.;.;.;.;Loss of phosphorylation at S424 (P = 0.0118);Loss of phosphorylation at S424 (P = 0.0118);
MVP		0.53
ClinPred		0.63	D
GERP RS		5.7
Varity_R		0.22
gMVP		0.69

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: rs193921096; hg19: chr4-86938505; COSMIC: COSV60376295; COSMIC: COSV60376295;