3-87240702-T-C

Variant names:

• chr3-87240702-T-C
• rs781703226
• NM_014043.4:c.38T>C

Variant summary

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

The NM_014043.4(CHMP2B):​c.38T>C​(p.Val13Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V13I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CHMP2B NM_014043.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.32
• 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=0.30893552).

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.38T>C	p.Val13Ala	missense	Exon 2 of 6	NP_054762.2
	CHMP2B	NM_001410777.1		c.134T>C	p.Val45Ala	missense	Exon 3 of 7	NP_001397706.1
	CHMP2B	NM_001244644.2		c.4-5012T>C		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.38T>C	p.Val13Ala	missense	Exon 2 of 6	ENSP00000263780.4	Q9UQN3-1
	CHMP2B	ENST00000472024.3	TSL:5	c.86T>C	p.Val29Ala	missense	Exon 3 of 7	ENSP00000480032.2	A0A087WW88
	CHMP2B	ENST00000676705.1		c.86T>C	p.Val29Ala	missense	Exon 3 of 7	ENSP00000504098.1	A0A087WW88

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251078 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 6.88e-7 AC: 1 AN: 1452550 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 723340

African (AFR) AF: 0.00 AC: 0 AN: 33280

American (AMR) AF: 0.0000224 AC: 1 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 86082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103606

Other (OTH) AF: 0.00 AC: 0 AN: 60072

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	0.97
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.64	N
PhyloP100		7.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.23
Sift	Benign	0.44	T
Sift4G	Benign	0.50	T
Polyphen		0.021	B
Vest4		0.58
MutPred		0.58		Loss of stability (P = 0.0104)
MVP		0.93
MPC		0.19
ClinPred		0.33	T
GERP RS		5.5
Varity_R		0.11
gMVP		0.29
Mutation Taster		=67/33	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: rs781703226; hg19: chr3-87289852;