rs2279720

chr3-87227549-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014043.4(CHMP2B):c.27C>T(p.Thr9=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0845 in 1,614,034 control chromosomes in the GnomAD database, including 6,606 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.093 (731 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5875 hom.)
• Consequence: CHMP2B NM_014043.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.155

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 3-87227549-C-T is Benign according to our data. Variant chr3-87227549-C-T is described in ClinVar as [Benign]. Clinvar id is 97999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-87227549-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.155 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHMP2B	NM_014043.4	c.27C>T	p.Thr9=	synonymous_variant	1/6	ENST00000263780.9
CHMP2B	NM_001244644.2	c.-5C>T		5_prime_UTR_variant	1/5
CHMP2B	NM_001410777.1	c.-5C>T		5_prime_UTR_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHMP2B	ENST00000263780.9	c.27C>T	p.Thr9=	synonymous_variant	1/6	1	NM_014043.4	P1

Frequencies

GnomAD3 genomes AF: 0.0927 AC: 14100 AN: 152078 Hom.: 727 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.0815

Gnomad FIN AF: 0.0474

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.0810

Gnomad OTH AF: 0.0961

GnomAD3 exomes AF: 0.0948 AC: 23734 AN: 250234 Hom.: 1401 AF XY: 0.0937 AC XY: 12679 AN XY: 135316

Gnomad AFR exome AF: 0.111

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.204

Gnomad SAS exome AF: 0.0836

Gnomad FIN exome AF: 0.0470

Gnomad NFE exome AF: 0.0796

Gnomad OTH exome AF: 0.0983

GnomAD4 exome AF: 0.0837 AC: 122286 AN: 1461838 Hom.: 5875 Cov.: 31 AF XY: 0.0842 AC XY: 61226 AN XY: 727216

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.108

Gnomad4 ASJ exome AF: 0.113

Gnomad4 EAS exome AF: 0.235

Gnomad4 SAS exome AF: 0.0839

Gnomad4 FIN exome AF: 0.0493

Gnomad4 NFE exome AF: 0.0763

Gnomad4 OTH exome AF: 0.0957

GnomAD4 genome AF: 0.0928 AC: 14123 AN: 152196 Hom.: 731 Cov.: 32 AF XY: 0.0922 AC XY: 6861 AN XY: 74382

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.100

Gnomad4 ASJ AF: 0.120

Gnomad4 EAS AF: 0.198

Gnomad4 SAS AF: 0.0804

Gnomad4 FIN AF: 0.0474

Gnomad4 NFE AF: 0.0810

Gnomad4 OTH AF: 0.0960

Alfa AF: 0.0869 Hom.: 937

Bravo AF: 0.0986

Asia WGS AF: 0.145 AC: 502 AN: 3478

EpiCase AF: 0.0887

EpiControl AF: 0.0877

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	- -
not provided, no classification provided	literature only	VIB Department of Molecular Genetics, University of Antwerp	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	13
Dann	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2279720; hg19: chr3-87276699; COSMIC: COSV55461881; COSMIC: COSV55461881;