22-50604558-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012324.6(MAPK8IP2):c.1259C>T(p.Pro420Leu) 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. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MAPK8IP2 NM_012324.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.26

Genes affected

MAPK8IP2 (HGNC:6883): (mitogen-activated protein kinase 8 interacting protein 2) This gene encodes a scaffold protein that is thought to be involved in the regulation of the c-Jun amino-terminal kinase signaling pathway. This protein has been shown to interact with and regulate the activity of MAPK8/JNK1 and MAP2K7/MKK7 kinases. [provided by RefSeq, Jun 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1725623).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAPK8IP2	NM_012324.6	c.1259C>T	p.Pro420Leu	missense_variant	5/12	ENST00000329492.6
MAPK8IP2	XM_011530679.3	c.1262C>T	p.Pro421Leu	missense_variant	5/12
MAPK8IP2	XM_011530680.3	c.1148C>T	p.Pro383Leu	missense_variant	5/12
MAPK8IP2	XM_011530681.3	c.1127C>T	p.Pro376Leu	missense_variant	5/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAPK8IP2	ENST00000329492.6	c.1259C>T	p.Pro420Leu	missense_variant	5/12	1	NM_012324.6	P1
MAPK8IP2	ENST00000008876.7	n.1178C>T		non_coding_transcript_exon_variant	3/10	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1013746 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 481514

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.1259C>T (p.P420L) alteration is located in exon 5 (coding exon 5) of the MAPK8IP2 gene. This alteration results from a C to T substitution at nucleotide position 1259, causing the proline (P) at amino acid position 420 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	16
Dann	Benign	0.95
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.71	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Pathogenic	0.88	D
REVEL	Benign	0.035
Sift4G	Benign	0.24	T
Polyphen		0.0010	B
Vest4		0.28
MutPred		0.24		Loss of glycosylation at P420 (P = 0.0025);
MVP		0.33
ClinPred		0.24	T
GERP RS		2.9
Varity_R		0.044
gMVP		0.26

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-51042986;