chr3-87240701-G-A

Variant names:

• chr3-87240701-G-A
• NM_014043.4:c.37G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014043.4(CHMP2B):​c.37G>A​(p.Val13Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V13E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHMP2B NM_014043.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20549434).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014043.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHMP2B	NM_014043.4	MANE Select	c.37G>A	p.Val13Ile	missense splice_region	Exon 2 of 6	NP_054762.2
	CHMP2B	NM_001410777.1		c.133G>A	p.Val45Ile	missense splice_region	Exon 3 of 7	NP_001397706.1
	CHMP2B	NM_001244644.2		c.4-5013G>A		intron	N/A	NP_001231573.1	Q9UQN3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHMP2B	ENST00000263780.9	TSL:1 MANE Select	c.37G>A	p.Val13Ile	missense splice_region	Exon 2 of 6	ENSP00000263780.4	Q9UQN3-1
	CHMP2B	ENST00000472024.3	TSL:5	c.85G>A	p.Val29Ile	missense splice_region	Exon 3 of 7	ENSP00000480032.2	A0A087WW88
	CHMP2B	ENST00000676705.1		c.85G>A	p.Val29Ile	missense splice_region	Exon 3 of 7	ENSP00000504098.1	A0A087WW88

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Frontotemporal dementia and/or amyotrophic lateral sclerosis 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.015
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.035	N
PhyloP100		3.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.28
Sift	Benign	0.49	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.55		Gain of catalytic residue at V13 (P = 0.0102)
MVP		0.88
MPC		0.12
ClinPred		0.64	D
GERP RS		5.5
Varity_R		0.057
gMVP		0.12
Mutation Taster		=79/21	polymorphism

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

hg19: chr3-87289851;