Variant 3-87253798-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP3_ModeratePP5BS2

The NM_014043.4(CHMP2B):c.618A>C(p.Gln206His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

CHMP2B
NM_014043.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1O:2

Conservation

PhyloP100: 1.48

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.886

PP5

Variant 3-87253798-A-C is Pathogenic according to our data. Variant chr3-87253798-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 1654.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-87253798-A-C is described in Lovd as [Pathogenic].

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CHMP2B	NM_014043.4 linkuse as main transcript	c.618A>C	p.Gln206His	missense_variant	6/6	ENST00000263780.9	NP_054762.2
CHMP2B	NM_001410777.1 linkuse as main transcript	c.714A>C	p.Gln238His	missense_variant	7/7		NP_001397706.1
CHMP2B	NM_001244644.2 linkuse as main transcript	c.495A>C	p.Gln165His	missense_variant	5/5		NP_001231573.1
CHMP2B	XM_011533576.3 linkuse as main transcript	c.666A>C	p.Gln222His	missense_variant	6/6		XP_011531878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHMP2B	ENST00000263780.9 linkuse as main transcript	c.618A>C	p.Gln206His	missense_variant	6/6	1	NM_014043.4	ENSP00000263780	P1	Q9UQN3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250526

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135396

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1460100

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726374

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000853

Hom.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 7

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 24, 2010	- -

not provided

Other:1

not provided, no classification provided

literature only

VIB Department of Molecular Genetics, University of Antwerp

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

.;T;T

Eigen

Benign

0.068

Eigen_PC

Benign

-0.051

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Uncertain

0.52

MutationAssessor

Uncertain

2.6

.;M;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.011

D;D;D

Sift4G

Uncertain

0.020

D;D;D

Polyphen

0.99

.;D;.

Vest4

0.64

MutPred

0.81

.;Loss of ubiquitination at K208 (P = 0.0505);.;

MVP

0.93

MPC

0.62

ClinPred

0.96

GERP RS

-2.6

Varity_R

0.66

gMVP

0.83

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over