chr3-87227554-A-G

Position:

• chr3-87227554-A-G

Variant summary

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

The NM_014043.4(CHMP2B):​c.32A>G​(p.Asp11Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000205 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CHMP2B NM_014043.4 missense, splice_region
• Scores: Splicing: ADA: 0.04843
• Clinical Significance: Uncertain significance no assertion criteria provided 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>G	p.Asp11Gly	missense_variant, splice_region_variant	1/6	ENST00000263780.9	NP_054762.2
CHMP2B	NM_001410777.1	c.1A>G	p.Met1?	start_lost, splice_region_variant	1/7		NP_001397706.1
CHMP2B	NM_001244644.2	c.1A>G	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>G	p.Asp11Gly	missense_variant, splice_region_variant	1/6	1	NM_014043.4	ENSP00000263780	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

CHMP2B-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2024

The CHMP2B c.1A>G variant is predicted to disrupt the translation initiation site (Start Loss). To our knowledge, this variant has not been reported in the literature or in gnomAD, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.080	T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.059
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.71	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.42	T
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.0	N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.017	D;D
Sift4G	Benign	0.062	T;T
Polyphen		0.0020	B;.
Vest4		0.55
MutPred		0.34		Loss of ubiquitination at K8 (P = 0.0551);Loss of ubiquitination at K8 (P = 0.0551);
MVP		0.92
MPC		0.20
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.40
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.048
dbscSNV1_RF	Benign	0.29
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

LitVar

Other links and lift over

dbSNP: rs921275036; hg19: chr3-87276704;