NM_014043.4:c.38T>A

Variant names:

• chr3-87240702-T-A
• NM_014043.4:c.38T>A

Variant summary

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

The NM_014043.4(CHMP2B):​c.38T>A​(p.Val13Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,452,550 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CHMP2B NM_014043.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.32

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP2B	NM_014043.4	c.38T>A	p.Val13Glu	missense_variant	Exon 2 of 6	ENST00000263780.9	NP_054762.2
CHMP2B	NM_001410777.1	c.134T>A	p.Val45Glu	missense_variant	Exon 3 of 7		NP_001397706.1
CHMP2B	XM_011533576.3	c.86T>A	p.Val29Glu	missense_variant	Exon 2 of 6		XP_011531878.1
CHMP2B	NM_001244644.2	c.4-5012T>A		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.38T>A	p.Val13Glu	missense_variant	Exon 2 of 6	1	NM_014043.4	ENSP00000263780.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1452550 Hom.: 0 Cov.: 28 AF XY: 0.00000276 AC XY: 2 AN XY: 723340

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: 0.00000362

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jul 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 13 of the CHMP2B protein (p.Val13Glu). This variant is not present in population databases (gnomAD no frequency). 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	Uncertain	0.44
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.056	T;T;T
Eigen	Benign	0.018
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T;D
M_CAP	Uncertain	0.096	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.0	L;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.83	N;N;.
REVEL	Uncertain	0.38
Sift	Benign	0.075	T;T;.
Sift4G	Benign	0.15	T;T;T
Polyphen		0.025	B;.;.
Vest4		0.63
MutPred		0.55		Loss of MoRF binding (P = 0.0235);Loss of MoRF binding (P = 0.0235);.;
MVP		0.94
MPC		0.32
ClinPred		0.87	D
GERP RS		5.5
Varity_R		0.32
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-87289852;