rs78268395

Positions:

• chr3-87253740-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014043.4(CHMP2B):​c.560G>A​(p.Ser187Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,612,490 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (7 hom.)
• Consequence: CHMP2B NM_014043.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.35

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]

CHMP2B (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006992072).
• BP6: Variant 3-87253740-G-A is Benign according to our data. Variant chr3-87253740-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-87253740-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00652 (991/151984) while in subpopulation AFR AF= 0.0226 (937/41494). AF 95% confidence interval is 0.0214. There are 10 homozygotes in gnomad4. There are 482 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 991 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHMP2B	NM_014043.4	c.560G>A	p.Ser187Asn	missense_variant	6/6	ENST00000263780.9	NP_054762.2
CHMP2B	NM_001410777.1	c.656G>A	p.Ser219Asn	missense_variant	7/7		NP_001397706.1
CHMP2B	NM_001244644.2	c.437G>A	p.Ser146Asn	missense_variant	5/5		NP_001231573.1
CHMP2B	XM_011533576.3	c.608G>A	p.Ser203Asn	missense_variant	6/6		XP_011531878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHMP2B	ENST00000263780.9	c.560G>A	p.Ser187Asn	missense_variant	6/6	1	NM_014043.4	ENSP00000263780.4

Frequencies

GnomAD3 genomes AF: 0.00653 AC: 992 AN: 151866 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00250

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00528

GnomAD3 exomes AF: 0.00153 AC: 384 AN: 250288 Hom.: 6 AF XY: 0.00113 AC XY: 153 AN XY: 135258

Gnomad AFR exome AF: 0.0203

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000605 AC: 883 AN: 1460506 Hom.: 7 Cov.: 30 AF XY: 0.000478 AC XY: 347 AN XY: 726538

Gnomad4 AFR exome AF: 0.0219

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.00652 AC: 991 AN: 151984 Hom.: 10 Cov.: 32 AF XY: 0.00649 AC XY: 482 AN XY: 74300

Gnomad4 AFR AF: 0.0226

Gnomad4 AMR AF: 0.00250

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.00127 Hom.: 3

Bravo AF: 0.00730

ESP6500AA AF: 0.0207 AC: 91

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00192 AC: 233

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 27, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 08, 2020	See Variant Classification Assertion Criteria. -

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

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.072	.;T;T
Eigen	Benign	-0.0080
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T;T;T
MetaRNN	Benign	0.0070	T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	1.7	.;L;.
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.40	N;N;N
REVEL	Benign	0.29
Sift	Benign	0.27	T;T;T
Sift4G	Benign	0.53	T;T;T
Polyphen		0.0040	.;B;.
Vest4		0.042
MVP		0.92
MPC		0.14
ClinPred		0.023	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs78268395; hg19: chr3-87302890;