3-87245899-T-C

Variant names:

• chr3-87245899-T-C
• rs11540913
• NM_014043.4:c.312T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014043.4(CHMP2B):​c.312T>C​(p.Thr104Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.919 in 1,610,386 control chromosomes in the GnomAD database, including 685,636 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (54744 hom., cov: 31)
  • Exomes 𝑓: 0.93 (630892 hom.)
• Consequence: CHMP2B NM_014043.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.616
• Publications: 27 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 3-87245899-T-C is Benign according to our data. Variant chr3-87245899-T-C is described in ClinVar as Benign. ClinVar VariationId is 98000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.616 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.936 is higher than 0.05.

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.312T>C	p.Thr104Thr	synonymous	Exon 3 of 6	NP_054762.2
	CHMP2B	NM_001410777.1		c.408T>C	p.Thr136Thr	synonymous	Exon 4 of 7	NP_001397706.1
	CHMP2B	NM_001244644.2		c.189T>C	p.Thr63Thr	synonymous	Exon 2 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.312T>C	p.Thr104Thr	synonymous	Exon 3 of 6	ENSP00000263780.4	Q9UQN3-1
	CHMP2B	ENST00000472024.3	TSL:5	c.360T>C	p.Thr120Thr	synonymous	Exon 4 of 7	ENSP00000480032.2	A0A087WW88
	CHMP2B	ENST00000676705.1		c.360T>C	p.Thr120Thr	synonymous	Exon 4 of 7	ENSP00000504098.1	A0A087WW88

Frequencies

GnomAD3 genomes AF: 0.833 AC: 126513 AN: 151922 Hom.: 54714 Cov.: 31

Gnomad AFR AF: 0.571

Gnomad AMI AF: 0.879

Gnomad AMR AF: 0.906

Gnomad ASJ AF: 0.921

Gnomad EAS AF: 0.899

Gnomad SAS AF: 0.936

Gnomad FIN AF: 0.928

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.942

Gnomad OTH AF: 0.849

GnomAD2 exomes AF: 0.912 AC: 228120 AN: 250244 AF XY: 0.919

Gnomad AFR exome AF: 0.569

Gnomad AMR exome AF: 0.934

Gnomad ASJ exome AF: 0.914

Gnomad EAS exome AF: 0.895

Gnomad FIN exome AF: 0.930

Gnomad NFE exome AF: 0.943

Gnomad OTH exome AF: 0.931

GnomAD4 exome AF: 0.928 AC: 1353673 AN: 1458346 Hom.: 630892 Cov.: 33 AF XY: 0.930 AC XY: 674936 AN XY: 725552

African (AFR) AF: 0.561 AC: 18714 AN: 33364

American (AMR) AF: 0.928 AC: 41374 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.914 AC: 23858 AN: 26098

East Asian (EAS) AF: 0.912 AC: 36147 AN: 39628

South Asian (SAS) AF: 0.945 AC: 81048 AN: 85790

European-Finnish (FIN) AF: 0.928 AC: 49564 AN: 53396

Middle Eastern (MID) AF: 0.925 AC: 5162 AN: 5580

European-Non Finnish (NFE) AF: 0.940 AC: 1042794 AN: 1109614

Other (OTH) AF: 0.913 AC: 55012 AN: 60278

GnomAD4 genome AF: 0.833 AC: 126595 AN: 152040 Hom.: 54744 Cov.: 31 AF XY: 0.837 AC XY: 62166 AN XY: 74308

African (AFR) AF: 0.572 AC: 23678 AN: 41424

American (AMR) AF: 0.905 AC: 13828 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.921 AC: 3195 AN: 3470

East Asian (EAS) AF: 0.899 AC: 4641 AN: 5162

South Asian (SAS) AF: 0.937 AC: 4516 AN: 4820

European-Finnish (FIN) AF: 0.928 AC: 9815 AN: 10582

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.942 AC: 64064 AN: 67992

Other (OTH) AF: 0.849 AC: 1792 AN: 2110

Alfa AF: 0.896 Hom.: 40965

Bravo AF: 0.817

Asia WGS AF: 0.891 AC: 3095 AN: 3474

EpiCase AF: 0.946

EpiControl AF: 0.943

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Frontotemporal dementia and/or amyotrophic lateral sclerosis 7 (3)
-	-	3	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.2
DANN	Benign	0.73
PhyloP100		-0.62
Mutation Taster		=99/1	polymorphism (auto)

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: rs11540913; hg19: chr3-87295049; COSMIC: COSV108021175;