rs63750818

Positions:

• chr3-87240749-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BS1_Supporting BS2

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. 14/21 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:6 O:2
• Conservation: PhyloP100: 2.17

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30391234).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000333 (486/1461450) while in subpopulation NFE AF= 0.000414 (460/1111704). AF 95% confidence interval is 0.000382. There are 0 homozygotes in gnomad4_exome. There are 226 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHMP2B	NM_014043.4	c.85A>G	p.Ile29Val	missense_variant	2/6	ENST00000263780.9	NP_054762.2
CHMP2B	NM_001410777.1	c.181A>G	p.Ile61Val	missense_variant	3/7		NP_001397706.1
CHMP2B	XM_011533576.3	c.133A>G	p.Ile45Val	missense_variant	2/6		XP_011531878.1
CHMP2B	NM_001244644.2	c.4-4965A>G		intron_variant			NP_001231573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHMP2B	ENST00000263780.9	c.85A>G	p.Ile29Val	missense_variant	2/6	1	NM_014043.4	ENSP00000263780	P1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152208 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000163 AC: 41 AN: 251262 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135802

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 SAS 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.: 0 Cov.: 29 AF XY: 0.000311 AC XY: 226 AN XY: 727066

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000414

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74362

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000341 Hom.: 0

Bravo AF: 0.000212

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000123 AC: 15

EpiCase AF: 0.000436

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

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

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 7 Pathogenic:1 Uncertain:3 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 25, 2023	ClinVar contains an entry for this variant (Variation ID: 21507). 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). This variant is present in population databases (rs63750818, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. 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). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHMP2B function (PMID: 20352044, 30766798). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Aug 07, 2018	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 24, 2010	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 11, 2018	The CHMP2B c.85A>G (p.Ile29Val) missense variant has been reported, across a selection of the available literature, in a heterozygous state in at least nine individuals with either frontotemporal dementia or amyotrophic lateral sclerosis (Rizzu et al. 2006; Cannon et al. 2006; Parkinson et al. 2006; Ferrari et al. 2010; Cox et al. 2010; Keogh et al. 2016; Morgan et al. 2017 Bartoletti-Stella et al. 2018). The p.Ile29Val variant has been reported in four of 2706 controls in a heterozygous state and is reported at a frequency of 0.00029 in the European (non-Finnish) population of the Genome Aggregation Database. Large cytoplasmic vacuoles, altered autophagy demonstrated by elevated amounts of LC3-II protein, and modified lysosomal localization seen through CD63 staining were all observed when the variant was transfected into HEK-293 and COS-7 cells; these changes were not seen for the wild type protein (Cox et al. 2010). Based on the evidence, the p.Ile29Val variant is classified as a variant of unknown significance but suspicious for pathogenicity for frontotemporal dementia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Uncertain:3 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 15, 2020	- -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2019	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CHMP2B: PM2:Supporting, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	15
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	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.34	N;.;.
MutationTaster	Benign	0.0025	A;A;A
PrimateAI	Uncertain	0.53	T
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	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.21

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

Other links and lift over

dbSNP: rs63750818; hg19: chr3-87289899;