Variant 13-48233476-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_021999.5(ITM2B):c.116A>G(p.Lys39Arg) variant causes a missense, splice region 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ITM2B
NM_021999.5 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.44

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:

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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/exons	MANE	Protein	UniProt
ITM2B	NM_021999.5 linkuse as main transcript	c.116A>G	p.Lys39Arg	missense_variant, splice_region_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.116A>G	p.Lys39Arg	missense_variant, splice_region_variant	1/6		NM_021999.5	ENSP00000497221.1		Q9Y287-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1372180

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

678002

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 01, 2024

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 39 of the ITM2B protein (p.Lys39Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ITM2B-related conditions. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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

0.087

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

T;.;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.77

.;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.6

L;L;L

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.0

N;N;.

REVEL

Benign

0.041

Sift

Benign

0.29

T;D;.

Sift4G

Benign

0.35

T;T;.

Polyphen

0.84

P;.;P

Vest4

0.24

MutPred

0.38

Gain of catalytic residue at V44 (P = 0.0018);Gain of catalytic residue at V44 (P = 0.0018);Gain of catalytic residue at V44 (P = 0.0018);

MVP

0.35

MPC

0.34

ClinPred

0.75

GERP RS

5.0

Varity_R

0.12

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.60

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.60

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over