13-48233448-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_021999.5(ITM2B):c.88C>T(p.Pro30Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,536,996 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P30T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00066 ( 2 hom., cov: 31)

Exomes 𝑓: 0.000041 ( 1 hom. )

Consequence

ITM2B
NM_021999.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.01

Publications

0 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028814465).

BP6

Variant 13-48233448-C-T is Benign according to our data. Variant chr13-48233448-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1670992.

BS2

High AC in GnomAd4 at 100 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.88C>T	p.Pro30Ser	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.88C>T	p.Pro30Ser	missense	Exon 1 of 6	ENSP00000497221.1	Q9Y287-1
ITM2B	ENST00000970638.1		c.88C>T	p.Pro30Ser	missense	Exon 1 of 7	ENSP00000640697.1
ITM2B	ENST00000899433.1		c.88C>T	p.Pro30Ser	missense	Exon 1 of 6	ENSP00000569492.1

Frequencies

GnomAD3 genomes

AF:

0.000658

AC:

100

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00649

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000238

AC:

AN:

138666

AF XY:

0.000237

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000412

AC:

AN:

1384910

Hom.:

Cov.:

AF XY:

0.0000321

AC XY:

AN XY:

684662

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28654

American (AMR)

AF:

0.00151

AC:

AN:

34420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24274

East Asian (EAS)

AF:

0.00

AC:

AN:

33218

South Asian (SAS)

AF:

0.00

AC:

AN:

77324

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48706

Middle Eastern (MID)

AF:

0.000178

AC:

AN:

5620

European-Non Finnish (NFE)

AF:

9.30e-7

AC:

AN:

1075470

Other (OTH)

AF:

0.0000524

AC:

AN:

57224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.000658

AC:

100

AN:

152086

Hom.:

Cov.:

AF XY:

0.000941

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41518

American (AMR)

AF:

0.00648

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67942

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000871

Hom.:

Bravo

AF:

0.000669

ExAC

AF:

0.00000869

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

ITM2B-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Benign

0.069

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.73

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.029

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

2.0

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.9

REVEL

Benign

0.061

Sift

Benign

0.22

Sift4G

Benign

0.21

Polyphen

0.68

Vest4

0.13

MutPred

0.47

Gain of catalytic residue at D32 (P = 0)

MVP

0.22

MPC

0.42

ClinPred

0.12

GERP RS

5.0

PromoterAI

-0.0060

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.12

gMVP

0.72

Mutation Taster

=90/10

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over