rs1044499

Variant names:

• chr3-87249925-A-C
• rs1044499
• NM_014043.4:c.372A>C

Your query was ambiguous. Multiple possible variants found:

• chr3-87249925-A-C
• chr3-87249925-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014043.4(CHMP2B):​c.372A>C​(p.Thr124Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0836 in 1,604,988 control chromosomes in the GnomAD database, including 6,491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (714 hom., cov: 32)
  • Exomes 𝑓: 0.083 (5777 hom.)
• Consequence: CHMP2B NM_014043.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.606
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• frontotemporal dementia and/or amyotrophic lateral sclerosis 7

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• amyotrophic lateral sclerosis type 17

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 3-87249925-A-C is Benign according to our data. Variant chr3-87249925-A-C is described in ClinVar as Benign. ClinVar VariationId is 98001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP2B	NM_014043.4	c.372A>C	p.Thr124Thr	synonymous_variant	Exon 4 of 6	ENST00000263780.9	NP_054762.2
CHMP2B	NM_001410777.1	c.468A>C	p.Thr156Thr	synonymous_variant	Exon 5 of 7		NP_001397706.1
CHMP2B	NM_001244644.2	c.249A>C	p.Thr83Thr	synonymous_variant	Exon 3 of 5		NP_001231573.1
CHMP2B	XM_011533576.3	c.420A>C	p.Thr140Thr	synonymous_variant	Exon 4 of 6		XP_011531878.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP2B	ENST00000263780.9	c.372A>C	p.Thr124Thr	synonymous_variant	Exon 4 of 6	1	NM_014043.4	ENSP00000263780.4

Frequencies

GnomAD3 genomes AF: 0.0916 AC: 13920 AN: 151946 Hom.: 711 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.0813

Gnomad FIN AF: 0.0474

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.0810

Gnomad OTH AF: 0.0952

GnomAD2 exomes AF: 0.0945 AC: 23558 AN: 249392 AF XY: 0.0934

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.204

Gnomad FIN exome AF: 0.0471

Gnomad NFE exome AF: 0.0795

Gnomad OTH exome AF: 0.0983

GnomAD4 exome AF: 0.0827 AC: 120176 AN: 1452922 Hom.: 5777 Cov.: 28 AF XY: 0.0833 AC XY: 60202 AN XY: 722730

African (AFR) AF: 0.109 AC: 3621 AN: 33238

American (AMR) AF: 0.107 AC: 4779 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 2922 AN: 25946

East Asian (EAS) AF: 0.235 AC: 9262 AN: 39384

South Asian (SAS) AF: 0.0834 AC: 7100 AN: 85102

European-Finnish (FIN) AF: 0.0491 AC: 2617 AN: 53266

Middle Eastern (MID) AF: 0.143 AC: 816 AN: 5720

European-Non Finnish (NFE) AF: 0.0754 AC: 83387 AN: 1105756

Other (OTH) AF: 0.0945 AC: 5672 AN: 59998

GnomAD4 genome AF: 0.0916 AC: 13936 AN: 152066 Hom.: 714 Cov.: 32 AF XY: 0.0910 AC XY: 6763 AN XY: 74320

African (AFR) AF: 0.104 AC: 4326 AN: 41516

American (AMR) AF: 0.0998 AC: 1525 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 415 AN: 3470

East Asian (EAS) AF: 0.199 AC: 1031 AN: 5172

South Asian (SAS) AF: 0.0801 AC: 387 AN: 4832

European-Finnish (FIN) AF: 0.0474 AC: 503 AN: 10620

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.0810 AC: 5496 AN: 67864

Other (OTH) AF: 0.0952 AC: 201 AN: 2112

Alfa AF: 0.0867 Hom.: 2677

Bravo AF: 0.0974

Asia WGS AF: 0.144 AC: 500 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

-

VIB Department of Molecular Genetics, University of Antwerp

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.5
DANN	Benign	0.69
PhyloP100		0.61
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1044499; hg19: chr3-87299075; COSMIC: COSV55461277; COSMIC: COSV55461277;