NM_014043.4:c.34+8C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_014043.4(CHMP2B):c.34+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,614,138 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 27 hom. )

Consequence

CHMP2B
NM_014043.4 splice_region, intron

Scores

Splicing: ADA: 0.00003953

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.496

Publications

2 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 3-87227564-C-T is Benign according to our data. Variant chr3-87227564-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 346804.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 441 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CHMP2B	NM_014043.4 link	c.34+8C>T	splice_region_variant, intron_variant	Intron 1 of 5	ENST00000263780.9	NP_054762.2	Q9UQN3-1B2RE76
CHMP2B	NM_001410777.1 link	c.3+8C>T	splice_region_variant, intron_variant	Intron 1 of 6		NP_001397706.1
CHMP2B	NM_001244644.2 link	c.3+8C>T	splice_region_variant, 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.34+8C>T		splice_region_variant, intron_variant	Intron 1 of 5	1	NM_014043.4	ENSP00000263780.4		Q9UQN3-1

Frequencies

GnomAD3 genomes

AF:

0.00290

AC:

441

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000844

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00550

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00273

AC:

682

AN:

249888

AF XY:

0.00256

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.00488

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00497

AC:

7265

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00477

AC XY:

3471

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.000657

AC:

AN:

33478

American (AMR)

AF:

0.00219

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000957

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000290

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000562

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00614

AC:

6829

AN:

1111986

Other (OTH)

AF:

0.00387

AC:

234

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

367

734

1102

1469

1836

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

258

516

774

1032

1290

<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:

0.00290

AC:

441

AN:

152278

Hom.:

Cov.:

AF XY:

0.00240

AC XY:

179

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.000842

AC:

AN:

41578

American (AMR)

AF:

0.00137

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00550

AC:

374

AN:

68018

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

100

125

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:

0.00410

Hom.:

Bravo

AF:

0.00272

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CHMP2B: BP4, BS2 -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 19, 2021

Athena Diagnostics

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

-0.88

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

-0.50

PromoterAI

-0.0052

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000040

dbscSNV1_RF

Benign

0.0040

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