Genetic Variant CHMP2B:p.Thr124Thr (chr3-87249925-A-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is . The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_014043.4(CHMP2B):c.372A>T(p.Thr124Thr) variant causes a synonymous 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T124T) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

CHMP2B
NM_014043.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.606

Publications

18 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, Ambry Genetics
amyotrophic lateral sclerosis type 17
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CHMP2B links:

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new If you want to explore the variant's impact on the transcript NM_014043.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP7

Synonymous conserved (PhyloP=0.606 with no splicing effect.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHMP2B	NM_014043.4	MANE Select	c.372A>T	p.Thr124Thr	synonymous	Exon 4 of 6	NP_054762.2
CHMP2B	NM_001410777.1		c.468A>T	p.Thr156Thr	synonymous	Exon 5 of 7	NP_001397706.1
CHMP2B	NM_001244644.2		c.249A>T	p.Thr83Thr	synonymous	Exon 3 of 5	NP_001231573.1	Q9UQN3-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHMP2B	ENST00000263780.9	TSL:1 MANE Select	c.372A>T	p.Thr124Thr	synonymous	Exon 4 of 6	ENSP00000263780.4	Q9UQN3-1
CHMP2B	ENST00000472024.3	TSL:5	c.420A>T	p.Thr140Thr	synonymous	Exon 5 of 7	ENSP00000480032.2	A0A087WW88
CHMP2B	ENST00000676705.1		c.420A>T	p.Thr140Thr	synonymous	Exon 5 of 7	ENSP00000504098.1	A0A087WW88

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

6.5

(source)

DANN

Benign

0.68

PhyloP100

0.61

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over