3-87227554-A-T

Position:

• chr3-87227554-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014043.4(CHMP2B):​c.32A>T​(p.Asp11Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHMP2B NM_014043.4 missense, splice_region
• Scores: Splicing: ADA: 0.02511
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.60

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHMP2B	NM_014043.4	c.32A>T	p.Asp11Val	missense_variant, splice_region_variant	1/6	ENST00000263780.9	NP_054762.2
CHMP2B	NM_001410777.1	c.1A>T	p.Met1?	start_lost, splice_region_variant	1/7		NP_001397706.1
CHMP2B	NM_001244644.2	c.1A>T	p.Met1?	start_lost, splice_region_variant	1/5		NP_001231573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHMP2B	ENST00000263780.9	c.32A>T	p.Asp11Val	missense_variant, splice_region_variant	1/6	1	NM_014043.4	ENSP00000263780	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 19, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with CHMP2B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 11 of the CHMP2B protein (p.Asp11Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Benign	0.95
DEOGEN2	Benign	0.082	T;T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.48	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-0.61	T
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.54
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.045	D;T
Polyphen		0.0050	B;.
Vest4		0.65
MutPred		0.38		Loss of disorder (P = 0.026);Loss of disorder (P = 0.026);
MVP		0.95
MPC		0.22
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.34
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.025
dbscSNV1_RF	Benign	0.18
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-87276704;