NM_014043.4:c.312T>C

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.312T>C(p.Thr104Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.919 in 1,610,386 control chromosomes in the GnomAD database, including 685,636 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.83 ( 54744 hom., cov: 31)

Exomes 𝑓: 0.93 ( 630892 hom. )

Consequence

CHMP2B
NM_014043.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10O:1

Conservation

PhyloP100: -0.616

Publications

27 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=-0.52).

BP6

Variant 3-87245899-T-C is Benign according to our data. Variant chr3-87245899-T-C is described in ClinVar as Benign. ClinVar VariationId is 98000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.616 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CHMP2B	NM_014043.4 link	c.312T>C	p.Thr104Thr	synonymous_variant	Exon 3 of 6	ENST00000263780.9	NP_054762.2
CHMP2B	NM_001410777.1 link	c.408T>C	p.Thr136Thr	synonymous_variant	Exon 4 of 7		NP_001397706.1
CHMP2B	NM_001244644.2 link	c.189T>C	p.Thr63Thr	synonymous_variant	Exon 2 of 5		NP_001231573.1
CHMP2B	XM_011533576.3 link	c.360T>C	p.Thr120Thr	synonymous_variant	Exon 3 of 6		XP_011531878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP2B	ENST00000263780.9 link	c.312T>C	p.Thr104Thr	synonymous_variant	Exon 3 of 6	1	NM_014043.4	ENSP00000263780.4

Frequencies

GnomAD3 genomes

AF:

0.833

AC:

126513

AN:

151922

Hom.:

54714

Cov.:

show subpopulations

Gnomad AFR

AF:

0.571

Gnomad AMI

AF:

0.879

Gnomad AMR

AF:

0.906

Gnomad ASJ

AF:

0.921

Gnomad EAS

AF:

0.899

Gnomad SAS

AF:

0.936

Gnomad FIN

AF:

0.928

Gnomad MID

AF:

0.896

Gnomad NFE

AF:

0.942

Gnomad OTH

AF:

0.849

GnomAD2 exomes

AF:

0.912

AC:

228120

AN:

250244

AF XY:

0.919

show subpopulations

Gnomad AFR exome

AF:

0.569

Gnomad AMR exome

AF:

0.934

Gnomad ASJ exome

AF:

0.914

Gnomad EAS exome

AF:

0.895

Gnomad FIN exome

AF:

0.930

Gnomad NFE exome

AF:

0.943

Gnomad OTH exome

AF:

0.931

GnomAD4 exome

AF:

0.928

AC:

1353673

AN:

1458346

Hom.:

630892

Cov.:

AF XY:

0.930

AC XY:

674936

AN XY:

725552

show subpopulations

African (AFR)

AF:

0.561

AC:

18714

AN:

33364

American (AMR)

AF:

0.928

AC:

41374

AN:

44598

Ashkenazi Jewish (ASJ)

AF:

0.914

AC:

23858

AN:

26098

East Asian (EAS)

AF:

0.912

AC:

36147

AN:

39628

South Asian (SAS)

AF:

0.945

AC:

81048

AN:

85790

European-Finnish (FIN)

AF:

0.928

AC:

49564

AN:

53396

Middle Eastern (MID)

AF:

0.925

AC:

5162

AN:

5580

European-Non Finnish (NFE)

AF:

0.940

AC:

1042794

AN:

1109614

Other (OTH)

AF:

0.913

AC:

55012

AN:

60278

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

4424

8848

13273

17697

22121

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21476

42952

64428

85904

107380

<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:

0.833

AC:

126595

AN:

152040

Hom.:

54744

Cov.:

AF XY:

0.837

AC XY:

62166

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.572

AC:

23678

AN:

41424

American (AMR)

AF:

0.905

AC:

13828

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.921

AC:

3195

AN:

3470

East Asian (EAS)

AF:

0.899

AC:

4641

AN:

5162

South Asian (SAS)

AF:

0.937

AC:

4516

AN:

4820

European-Finnish (FIN)

AF:

0.928

AC:

9815

AN:

10582

Middle Eastern (MID)

AF:

0.898

AC:

264

AN:

294

European-Non Finnish (NFE)

AF:

0.942

AC:

64064

AN:

67992

Other (OTH)

AF:

0.849

AC:

1792

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

873

1747

2620

3494

4367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

864

1728

2592

3456

4320

<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:

0.896

Hom.:

40965

Bravo

AF:

0.817

Asia WGS

AF:

0.891

AC:

3095

AN:

3474

EpiCase

AF:

0.946

EpiControl

AF:

0.943

ClinVar

Significance: Benign

Submissions summary: Benign:10Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3Other:1

Nov 17, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 03, 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

- -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 7

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

5.2

(source)

DANN

Benign

0.73

PhyloP100

-0.62

Mutation Taster

=99/1

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