13-48233452-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P31H) has been classified as Benign.

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

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

ABri amyloidosis
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
ADan amyloidosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ITM2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

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

BS2

High AC in GnomAd4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021999.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITM2B	NM_021999.5	MANE Select	c.92C>G	p.Pro31Arg	missense	Exon 1 of 6	NP_068839.1	Q9Y287-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ITM2B	ENST00000647800.2	MANE Select	c.92C>G	p.Pro31Arg	missense	Exon 1 of 6	ENSP00000497221.1	Q9Y287-1
ITM2B	ENST00000970638.1		c.92C>G	p.Pro31Arg	missense	Exon 1 of 7	ENSP00000640697.1
ITM2B	ENST00000899433.1		c.92C>G	p.Pro31Arg	missense	Exon 1 of 6	ENSP00000569492.1

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

GnomAD2 exomes

AF:

0.0000917

AC:

AN:

141742

AF XY:

0.0000387

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 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

African (AFR)

AF:

0.0000699

AC:

AN:

28614

American (AMR)

AF:

0.000233

AC:

AN:

34272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24276

East Asian (EAS)

AF:

0.0000302

AC:

AN:

33118

South Asian (SAS)

AF:

0.0000518

AC:

AN:

77238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48658

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5618

European-Non Finnish (NFE)

AF:

0.000121

AC:

130

AN:

1074800

Other (OTH)

AF:

0.000157

AC:

AN:

57202

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41526

American (AMR)

AF:

0.000196

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67974

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.569

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.0000609

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

ADan amyloidosis;C4015146:Retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies;C5190835:ABri amyloidosis (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.26

Eigen

Benign

-0.062

Eigen_PC

Benign

0.018

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.71

M_CAP

Benign

0.075

MetaRNN

Benign

0.018

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.9

PhyloP100

2.8

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.3

REVEL

Benign

0.026

Sift

Benign

0.28

Sift4G

Benign

0.37

Polyphen

0.45

Vest4

0.36

MutPred

0.39

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

MVP

0.22

MPC

0.55

ClinPred

0.065

GERP RS

4.2

PromoterAI

0.057

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

Varity_R

0.083

gMVP

0.60

Mutation Taster

=78/22

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over