rs281864934

Positions:

• chr3-87245898-C-A
• chr3-87245898-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The ENST00000263780.9(CHMP2B):​c.311C>A​(p.Thr104Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. T104T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHMP2B ENST00000263780.9 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.57

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797
• PP5: Variant 3-87245898-C-A is Pathogenic according to our data. Variant chr3-87245898-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 35472.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHMP2B	NM_014043.4	c.311C>A	p.Thr104Asn	missense_variant	3/6	ENST00000263780.9	NP_054762.2
CHMP2B	NM_001410777.1	c.407C>A	p.Thr136Asn	missense_variant	4/7		NP_001397706.1
CHMP2B	NM_001244644.2	c.188C>A	p.Thr63Asn	missense_variant	2/5		NP_001231573.1
CHMP2B	XM_011533576.3	c.359C>A	p.Thr120Asn	missense_variant	3/6		XP_011531878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHMP2B	ENST00000263780.9	c.311C>A	p.Thr104Asn	missense_variant	3/6	1	NM_014043.4	ENSP00000263780	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458752 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725762

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

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

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.23	.;T;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.6	.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.3	N;N;.
REVEL	Benign	0.23
Sift	Benign	0.15	T;T;.
Sift4G	Benign	0.50	T;T;T
Polyphen		0.32	.;B;.
Vest4		0.52
MutPred		0.78		.;Loss of catalytic residue at T104 (P = 0.0483);.;
MVP		0.90
MPC		0.46
ClinPred		0.94	D
GERP RS		5.0
Varity_R		0.41
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs281864934; hg19: chr3-87295048;