13-48233452-C-G

Position:

chr13-48233452-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_021999.5(ITM2B):c.92C>G(p.Pro31Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,535,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

ITM2B
NM_021999.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.80

Variant links:

Genes affected

ITM2B (HGNC:6174): (integral membrane protein 2B) Amyloid precursor proteins are processed by beta-secretase and gamma-secretase to produce beta-amyloid peptides which form the characteristic plaques of Alzheimer disease. This gene encodes a transmembrane protein which is processed at the C-terminus by furin or furin-like proteases to produce a small secreted peptide which inhibits the deposition of beta-amyloid. Mutations which result in extension of the C-terminal end of the encoded protein, thereby increasing the size of the secreted peptide, are associated with two neurogenerative diseases, familial British dementia and familial Danish dementia. [provided by RefSeq, Oct 2009]

ITM2B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01826939).

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITM2B	NM_021999.5 linkuse as main transcript	c.92C>G	p.Pro31Arg	missense_variant	1/6	ENST00000647800.2	NP_068839.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITM2B	ENST00000647800.2 linkuse as main transcript	c.92C>G	p.Pro31Arg	missense_variant	1/6		NM_021999.5	ENSP00000497221.1		Q9Y287-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.0000917

AC:

AN:

141742

Hom.:

AF XY:

0.0000387

AC XY:

AN XY:

77604

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000399

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000482

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000519

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000111

AC:

154

AN:

1383796

Hom.:

Cov.:

AF XY:

0.0000994

AC XY:

AN XY:

684002

show subpopulations

Gnomad4 AFR exome

AF:

0.0000699

Gnomad4 AMR exome

AF:

0.000233

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000302

Gnomad4 SAS exome

AF:

0.0000518

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.000157

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000106

ExAC

AF:

0.0000609

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ADan amyloidosis;C4015146:Retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies;C5190835:ABri amyloidosis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 14, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 06, 2023

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 31 of the ITM2B protein (p.Pro31Arg). This variant is present in population databases (rs150336652, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with small vessel disease stroke (PMID: 31719132). ClinVar contains an entry for this variant (Variation ID: 1353049). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.26

T;.;T

Eigen

Benign

-0.062

Eigen_PC

Benign

0.018

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.71

.;T;T

M_CAP

Benign

0.075

MetaRNN

Benign

0.018

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.9

L;L;L

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.3

N;N;.

REVEL

Benign

0.026

Sift

Benign

0.28

T;D;.

Sift4G

Benign

0.37

T;T;.

Polyphen

0.45

P;.;P

Vest4

0.36

MutPred

0.39

Gain of catalytic residue at A33 (P = 2e-04);Gain of catalytic residue at A33 (P = 2e-04);Gain of catalytic residue at A33 (P = 2e-04);

MVP

0.22

MPC

0.55

ClinPred

0.065

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Varity_R

0.083

gMVP

0.60

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