rs63750653

Positions:

• chr3-87253421-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014043.4(CHMP2B):​c.442G>T​(p.Asp148Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,454,482 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHMP2B NM_014043.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1 O:2
• Conservation: PhyloP100: 9.56

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHMP2B	NM_014043.4	c.442G>T	p.Asp148Tyr	missense_variant	5/6	ENST00000263780.9
CHMP2B	NM_001410777.1	c.538G>T	p.Asp180Tyr	missense_variant	6/7
CHMP2B	NM_001244644.2	c.319G>T	p.Asp107Tyr	missense_variant	4/5
CHMP2B	XM_011533576.3	c.490G>T	p.Asp164Tyr	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHMP2B	ENST00000263780.9	c.442G>T	p.Asp148Tyr	missense_variant	5/6	1	NM_014043.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1454482 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 724052

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: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

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

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 148 of the CHMP2B protein (p.Asp148Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with frontotemporal dementia (PMID: 16041373). ClinVar contains an entry for this variant (Variation ID: 1653). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHMP2B function (PMID: 17956895). 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2005	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Other:1

not provided, no classification provided

literature only

VIB Department of Molecular Genetics, University of Antwerp

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Uncertain	0.37	D
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.0	D;D;D;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0050	D;D;D;.
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		0.91	.;P;.;.
Vest4		0.63
MutPred		0.82		.;Loss of helix (P = 0.0444);.;.;
MVP		0.92
MPC		0.64
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.96

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: rs63750653; hg19: chr3-87302571;