chr13-48233449-C-T

Position:

• chr13-48233449-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021999.5(ITM2B):​c.89C>T​(p.Pro30Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ITM2B NM_021999.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.85

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3840897).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITM2B	NM_021999.5	c.89C>T	p.Pro30Leu	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	c.89C>T	p.Pro30Leu	missense_variant	1/6		NM_021999.5	ENSP00000497221.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 07, 2022

This variant has not been reported in the literature in individuals affected with ITM2B-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1389380). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 30 of the ITM2B protein (p.Pro30Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.34	T;.;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.84	.;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;L
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.6	D;D;.
REVEL	Benign	0.10
Sift	Benign	0.11	T;D;.
Sift4G	Benign	0.14	T;D;.
Polyphen		0.81	P;.;P
Vest4		0.28
MutPred		0.52		Gain of catalytic residue at D32 (P = 4e-04);Gain of catalytic residue at D32 (P = 4e-04);Gain of catalytic residue at D32 (P = 4e-04);
MVP		0.18
MPC		0.48
ClinPred		0.89	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.13
gMVP		0.74

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

Other links and lift over

dbSNP: rs1479180708; hg19: chr13-48807585;