Variant 11-45902420-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000241014.6(MAPK8IP1):c.653C>T(p.Pro218Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000347 in 1,584,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

MAPK8IP1
ENST00000241014.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.03

Variant links:

Genes affected

MAPK8IP1 (HGNC:6882): (mitogen-activated protein kinase 8 interacting protein 1) This gene encodes a regulator of the pancreatic beta-cell function. It is highly similar to JIP-1, a mouse protein known to be a regulator of c-Jun amino-terminal kinase (Mapk8). This protein has been shown to prevent MAPK8 mediated activation of transcription factors, and to decrease IL-1 beta and MAP kinase kinase 1 (MEKK1) induced apoptosis in pancreatic beta cells. This protein also functions as a DNA-binding transactivator of the glucose transporter GLUT2. RE1-silencing transcription factor (REST) is reported to repress the expression of this gene in insulin-secreting beta cells. This gene is found to be mutated in a type 2 diabetes family, and thus is thought to be a susceptibility gene for type 2 diabetes. [provided by RefSeq, May 2011]

MAPK8IP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10113695).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAPK8IP1	NM_005456.4 linkuse as main transcript	c.653C>T	p.Pro218Leu	missense_variant	5/12	ENST00000241014.6	NP_005447.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MAPK8IP1	ENST00000241014.6 linkuse as main transcript	c.653C>T	p.Pro218Leu	missense_variant	5/12	1	NM_005456.4	ENSP00000241014	P4
MAPK8IP1	ENST00000395629.2 linkuse as main transcript	c.623C>T	p.Pro208Leu	missense_variant	5/12	5		ENSP00000378991	A1
MAPK8IP1	ENST00000497090.1 linkuse as main transcript	n.178C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000665

AC:

AN:

195364

Hom.:

AF XY:

0.0000658

AC XY:

AN XY:

106308

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000172

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000304

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1432858

Hom.:

Cov.:

AF XY:

0.0000324

AC XY:

AN XY:

710164

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000125

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000217

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000237

Gnomad4 OTH exome

AF:

0.0000169

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152090

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000330

Hom.:

ExAC

AF:

0.0000502

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 06, 2024

The c.653C>T (p.P218L) alteration is located in exon 5 (coding exon 5) of the MAPK8IP1 gene. This alteration results from a C to T substitution at nucleotide position 653, causing the proline (P) at amino acid position 218 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

0.072

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;T

Eigen

Benign

-0.12

Eigen_PC

Benign

0.060

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.82

T;T

M_CAP

Benign

0.0088

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

N;.

MutationTaster

Benign

0.92

D;D

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-2.4

N;N

REVEL

Benign

0.019

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.022

D;D

Polyphen

0.063

B;.

Vest4

0.42

MutPred

0.17

Loss of glycosylation at P218 (P = 0.0253);.;

MVP

0.38

MPC

0.44

ClinPred

0.10

GERP RS

4.5

Varity_R

0.12

gMVP

0.12

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over