3-87240692-C-T

Variant names:

• chr3-87240692-C-T
• rs200912994
• NM_014043.4:c.35-7C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_014043.4(CHMP2B):​c.35-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,586,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CHMP2B NM_014043.4 splice_region, intron
• Scores: Splicing: ADA: 0.0004617
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.881

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 3-87240692-C-T is Benign according to our data. Variant chr3-87240692-C-T is described in ClinVar as [Benign]. Clinvar id is 704275.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 186 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP2B	NM_014043.4	c.35-7C>T		splice_region_variant, intron_variant	Intron 1 of 5	ENST00000263780.9	NP_054762.2
CHMP2B	NM_001410777.1	c.131-7C>T		splice_region_variant, intron_variant	Intron 2 of 6		NP_001397706.1
CHMP2B	NM_001244644.2	c.4-5022C>T		intron_variant	Intron 1 of 4		NP_001231573.1
CHMP2B	XM_011533576.3	c.83-7C>T		splice_region_variant, intron_variant	Intron 1 of 5		XP_011531878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP2B	ENST00000263780.9	c.35-7C>T		splice_region_variant, intron_variant	Intron 1 of 5	1	NM_014043.4	ENSP00000263780.4

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00413

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000355 AC: 89 AN: 251010 Hom.: 0 AF XY: 0.000243 AC XY: 33 AN XY: 135670

Gnomad AFR exome AF: 0.00438

Gnomad AMR exome AF: 0.000492

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: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000110 AC: 158 AN: 1433970 Hom.: 0 Cov.: 26 AF XY: 0.0000866 AC XY: 62 AN XY: 715546

Gnomad4 AFR exome AF: 0.00368

Gnomad4 AMR exome AF: 0.000381

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: 0.00000184

Gnomad4 OTH exome AF: 0.000286

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74406

Gnomad4 AFR AF: 0.00412

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000589 Hom.: 0

Bravo AF: 0.00150

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 7 Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CHMP2B-related disorder Benign:1

Nov 30, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CHMP2B: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	11
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00046
dbscSNV1_RF	Benign	0.022
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: rs200912994; hg19: chr3-87289842;