rs2279720

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_014043.4(CHMP2B):c.27C>T(p.Thr9Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0845 in 1,614,034 control chromosomes in the GnomAD database, including 6,606 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.093 ( 731 hom., cov: 32)

Exomes 𝑓: 0.084 ( 5875 hom. )

Consequence

CHMP2B
NM_014043.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: -0.155

Publications

19 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 3-87227549-C-T is Benign according to our data. Variant chr3-87227549-C-T is described in ClinVar as Benign. ClinVar VariationId is 97999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.155 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP2B	NM_014043.4 link	c.27C>T	p.Thr9Thr	synonymous_variant	Exon 1 of 6	ENST00000263780.9	NP_054762.2	Q9UQN3-1B2RE76

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP2B	ENST00000263780.9 link	c.27C>T	p.Thr9Thr	synonymous_variant	Exon 1 of 6	1	NM_014043.4	ENSP00000263780.4		Q9UQN3-1

Frequencies

GnomAD3 genomes

AF:

0.0927

AC:

14100

AN:

152078

Hom.:

727

Cov.:

show subpopulations

Gnomad AFR

AF:

0.108

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.100

Gnomad ASJ

AF:

0.120

Gnomad EAS

AF:

0.198

Gnomad SAS

AF:

0.0815

Gnomad FIN

AF:

0.0474

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.0810

Gnomad OTH

AF:

0.0961

GnomAD2 exomes

AF:

0.0948

AC:

23734

AN:

250234

AF XY:

0.0937

show subpopulations

Gnomad AFR exome

AF:

0.111

Gnomad AMR exome

AF:

0.112

Gnomad ASJ exome

AF:

0.116

Gnomad EAS exome

AF:

0.204

Gnomad FIN exome

AF:

0.0470

Gnomad NFE exome

AF:

0.0796

Gnomad OTH exome

AF:

0.0983

GnomAD4 exome

AF:

0.0837

AC:

122286

AN:

1461838

Hom.:

5875

Cov.:

AF XY:

0.0842

AC XY:

61226

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.113

AC:

3791

AN:

33478

American (AMR)

AF:

0.108

AC:

4829

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.113

AC:

2953

AN:

26136

East Asian (EAS)

AF:

0.235

AC:

9346

AN:

39700

South Asian (SAS)

AF:

0.0839

AC:

7239

AN:

86256

European-Finnish (FIN)

AF:

0.0493

AC:

2636

AN:

53418

Middle Eastern (MID)

AF:

0.145

AC:

838

AN:

5768

European-Non Finnish (NFE)

AF:

0.0763

AC:

84874

AN:

1111964

Other (OTH)

AF:

0.0957

AC:

5780

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

6129

12259

18388

24518

30647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3230

6460

9690

12920

16150

<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:

0.0928

AC:

14123

AN:

152196

Hom.:

731

Cov.:

AF XY:

0.0922

AC XY:

6861

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.108

AC:

4506

AN:

41536

American (AMR)

AF:

0.100

AC:

1533

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.120

AC:

416

AN:

3472

East Asian (EAS)

AF:

0.198

AC:

1015

AN:

5118

South Asian (SAS)

AF:

0.0804

AC:

387

AN:

4816

European-Finnish (FIN)

AF:

0.0474

AC:

503

AN:

10622

Middle Eastern (MID)

AF:

0.160

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0810

AC:

5508

AN:

68018

Other (OTH)

AF:

0.0960

AC:

203

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

656

1312

1967

2623

3279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

160

320

480

640

800

<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:

0.0877

Hom.:

1373

Bravo

AF:

0.0986

Asia WGS

AF:

0.145

AC:

502

AN:

3478

EpiCase

AF:

0.0887

EpiControl

AF:

0.0877

ClinVar

Significance: Benign

Submissions summary: Benign:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2Other:1

Aug 17, 2018

GeneDx

Significance:Benign

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 7

Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

-0.15

PromoterAI

-0.047

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=296/4

polymorphism (auto)

(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