3-87227550-G-A

Variant names:

• chr3-87227550-G-A
• rs1295215037
• NM_014043.4:c.28G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001410777.1(CHMP2B):​c.-4G>A variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000137 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHMP2B NM_001410777.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.92
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35415795).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001410777.1. 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.28G>A	p.Val10Met	missense	Exon 1 of 6	NP_054762.2
	CHMP2B	NM_001410777.1		c.-4G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001397706.1
	CHMP2B	NM_001244644.2		c.-4G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	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.28G>A	p.Val10Met	missense	Exon 1 of 6	ENSP00000263780.4	Q9UQN3-1
	CHMP2B	ENST00000472024.3	TSL:5	c.-56G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000480032.2	A0A087WW88
	CHMP2B	ENST00000676705.1		c.-52G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000504098.1	A0A087WW88

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250246 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

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	Uncertain	0.37
BayesDel_addAF	Benign	-0.0016	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.012
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.020	D
MutationAssessor	Benign	1.7	L
PhyloP100		3.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.56	N
REVEL	Uncertain	0.48
Sift	Benign	0.11	T
Sift4G	Benign	0.13	T
Polyphen		0.095	B
Vest4		0.47
MutPred		0.55		Gain of catalytic residue at V10 (P = 0.0037)
MVP		0.90
MPC		0.18
ClinPred		0.62	D
GERP RS		4.2
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.46
Mutation Taster		=84/16	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

dbSNP: rs1295215037; hg19: chr3-87276700;