rs63750818

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_014043.4(CHMP2B):c.85A>G(p.Ile29Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,613,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

CHMP2B
NM_014043.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:6O:2

Conservation

PhyloP100: 2.17

Publications

30 publications found

Variant links:

Genes affected

CHMP2B (HGNC:24537): (charged multivesicular body protein 2B) This gene encodes a component of the heteromeric ESCRT-III complex (Endosomal Sorting Complex Required for Transport III) that functions in the recycling or degradation of cell surface receptors. ESCRT-III functions in the concentration and invagination of ubiquitinated endosomal cargos into intralumenal vesicles. The protein encoded by this gene is found as a monomer in the cytosol or as an oligomer in ESCRT-III complexes on endosomal membranes. It is expressed in neurons of all major regions of the brain. Mutations in this gene result in one form of familial frontotemporal lobar degeneration. [provided by RefSeq, Jul 2008]

CHMP2B Gene-Disease associations (from GenCC):

frontotemporal dementia and/or amyotrophic lateral sclerosis 7
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
amyotrophic lateral sclerosis type 17
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CHMP2B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30391234).

BS2

High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP2B	NM_014043.4 link	c.85A>G	p.Ile29Val	missense_variant	Exon 2 of 6	ENST00000263780.9	NP_054762.2	Q9UQN3-1B2RE76
CHMP2B	NM_001410777.1 link	c.181A>G	p.Ile61Val	missense_variant	Exon 3 of 7		NP_001397706.1
CHMP2B	XM_011533576.3 link	c.133A>G	p.Ile45Val	missense_variant	Exon 2 of 6		XP_011531878.1	A0A087WW88
CHMP2B	NM_001244644.2 link	c.4-4965A>G		intron_variant	Intron 1 of 4		NP_001231573.1	Q9UQN3-2B2RE76

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP2B	ENST00000263780.9 link	c.85A>G	p.Ile29Val	missense_variant	Exon 2 of 6	1	NM_014043.4	ENSP00000263780.4		Q9UQN3-1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000353

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000163

AC:

AN:

251262

AF XY:

0.000169

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000291

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000333

AC:

486

AN:

1461450

Hom.:

Cov.:

AF XY:

0.000311

AC XY:

226

AN XY:

727066

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33464

American (AMR)

AF:

0.0000895

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000414

AC:

460

AN:

1111704

Other (OTH)

AF:

0.000265

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.000191

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74362

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41440

American (AMR)

AF:

0.000131

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000345

Hom.:

Bravo

AF:

0.000212

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:6Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 7

Pathogenic:1Uncertain:3Other:1

Aug 06, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 29 of the CHMP2B protein (p.Ile29Val). This variant is present in population databases (rs63750818, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with amyotrophic lateral sclerosis, dementia with Lewy bodies and primary muscular atrophy (PMID: 16431024, 16807408, 16941655, 20352044, 21222599, 26836416, 28430856, 29431110, 29525180, 35896380). ClinVar contains an entry for this variant (Variation ID: 21507). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHMP2B function (PMID: 20352044, 30766798). 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. -

Mar 24, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:3Other:1

Apr 15, 2020

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

VIB Department of Molecular Genetics, University of Antwerp

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Sep 25, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect indicating that this alteration results in cells with more large cytoplasmic vacuoles, mislocalization of the CHMP2B protein to the outer membrane, and defects in the autophagy pathway (Cox et al., 2010); The Alzheimer Disease and Frontotemporal Dementia Mutation Database classifies this variant as pathogenic nature unclear (Cruts et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16807408, 16431024, 20352044, 26836416, 21222599, 28430856, 29525180, 29431110, 30766798, 29916020, 31996268) -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CHMP2B: PM2:Supporting, BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.20

T;T;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.77

T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.30

T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.34

N;.;.

PhyloP100

2.2

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.72

N;N;.

REVEL

Uncertain

0.35

Sift

Benign

0.16

T;T;.

Sift4G

Uncertain

0.038

D;D;T

Polyphen

0.0

B;.;.

Vest4

0.20

MVP

0.81

MPC

0.12

ClinPred

0.018

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.037

gMVP

0.21

Mutation Taster

=35/65

disease causing

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over