Genetic Variant NM_001170687.4:c.148C>T (chr1-1623600-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001170687.4(MIB2):c.148C>T(p.Arg50Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000326 in 1,503,890 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000034 ( 1 hom. )

Consequence

MIB2
NM_001170687.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.31

Variant links:

Genes affected

MIB2 (HGNC:30577): (MIB E3 ubiquitin protein ligase 2) The protein encoded by this gene is an E3 ubiquitin protein ligase that mediates ubiquitination of proteins in the Notch signaling pathway. The encoded protein may be a suppressor of melanoma invasion. [provided by RefSeq, Mar 2017]

MIB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIB2	NM_001170687.4 link	c.148C>T	p.Arg50Cys	missense_variant	Exon 3 of 20	ENST00000355826.10	NP_001164158.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MIB2	ENST00000355826.10 link	c.148C>T	p.Arg50Cys	missense_variant	Exon 3 of 20	1	NM_001170687.4	ENSP00000348081.6		Q96AX9-1E9PD12

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152214

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000104

AC:

AN:

105654

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

56940

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000264

Gnomad OTH exome

AF:

0.000314

GnomAD4 exome

AF:

0.0000340

AC:

AN:

1351676

Hom.:

Cov.:

AF XY:

0.0000423

AC XY:

AN XY:

662598

show subpopulations

Gnomad4 AFR exome

AF:

0.0000330

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000136

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000397

Gnomad4 OTH exome

AF:

0.0000357

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000435

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.493C>T (p.R165C) alteration is located in exon 3 (coding exon 3) of the MIB2 gene. This alteration results from a C to T substitution at nucleotide position 493, causing the arginine (R) at amino acid position 165 to be replaced by a cysteine (C). 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

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

.;.;.;.;.;.;.;T;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.79

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Uncertain

0.60

D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.35

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.0

D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.0010

D;D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D

Vest4

0.36

MVP

0.79

MPC

1.5

ClinPred

0.76

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.47

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

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