NM_014043.4:c.36T>G

Variant names:

• chr3-87240700-T-G
• rs141196445
• NM_014043.4:c.36T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014043.4(CHMP2B):​c.36T>G​(p.Asp12Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,451,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHMP2B NM_014043.4 missense, splice_region
• Scores: Splicing: ADA: 0.006131
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.43

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2126525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP2B	NM_014043.4	c.36T>G	p.Asp12Glu	missense_variant, splice_region_variant	Exon 2 of 6	ENST00000263780.9	NP_054762.2
CHMP2B	NM_001410777.1	c.132T>G	p.Asp44Glu	missense_variant, splice_region_variant	Exon 3 of 7		NP_001397706.1
CHMP2B	XM_011533576.3	c.84T>G	p.Asp28Glu	missense_variant, splice_region_variant	Exon 2 of 6		XP_011531878.1
CHMP2B	NM_001244644.2	c.4-5014T>G		intron_variant	Intron 1 of 4		NP_001231573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP2B	ENST00000263780.9	c.36T>G	p.Asp12Glu	missense_variant, splice_region_variant	Exon 2 of 6	1	NM_014043.4	ENSP00000263780.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251052 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135674

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451746 Hom.: 0 Cov.: 28 AF XY: 0.00000277 AC XY: 2 AN XY: 723132

Gnomad4 AFR exome AF: 0.00

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000172 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Sep 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 12 of the CHMP2B protein (p.Asp12Glu). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CHMP2B-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0032	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Benign	0.61
DEOGEN2	Benign	0.054	T;T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	-0.22	N;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	1.3	N;N;.
REVEL	Uncertain	0.33
Sift	Benign	1.0	T;T;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.65
MutPred		0.43		Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);.;
MVP		0.87
MPC		0.15
ClinPred		0.21	T
GERP RS		5.5
Varity_R		0.26
gMVP		0.040

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0061
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.36		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs141196445; hg19: chr3-87289850;