NM_014043.4:c.372A>C

Variant names:

• chr3-87249925-A-C
• rs1044499
• NM_014043.4:c.372A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014043.4(CHMP2B):​c.372A>C​(p.Thr124Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0836 in 1,604,988 control chromosomes in the GnomAD database, including 6,491 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (714 hom., cov: 32)
  • Exomes 𝑓: 0.083 (5777 hom.)
• Consequence: CHMP2B NM_014043.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.606
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 3-87249925-A-C is Benign according to our data. Variant chr3-87249925-A-C is described in ClinVar as Benign. ClinVar VariationId is 98001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.189 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.372A>C	p.Thr124Thr	synonymous	Exon 4 of 6	NP_054762.2
	CHMP2B	NM_001410777.1		c.468A>C	p.Thr156Thr	synonymous	Exon 5 of 7	NP_001397706.1
	CHMP2B	NM_001244644.2		c.249A>C	p.Thr83Thr	synonymous	Exon 3 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.372A>C	p.Thr124Thr	synonymous	Exon 4 of 6	ENSP00000263780.4	Q9UQN3-1
	CHMP2B	ENST00000472024.3	TSL:5	c.420A>C	p.Thr140Thr	synonymous	Exon 5 of 7	ENSP00000480032.2	A0A087WW88
	CHMP2B	ENST00000676705.1		c.420A>C	p.Thr140Thr	synonymous	Exon 5 of 7	ENSP00000504098.1	A0A087WW88

Frequencies

GnomAD3 genomes AF: 0.0916 AC: 13920 AN: 151946 Hom.: 711 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.0813

Gnomad FIN AF: 0.0474

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.0810

Gnomad OTH AF: 0.0952

GnomAD2 exomes AF: 0.0945 AC: 23558 AN: 249392 AF XY: 0.0934

Gnomad AFR exome AF: 0.108

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.204

Gnomad FIN exome AF: 0.0471

Gnomad NFE exome AF: 0.0795

Gnomad OTH exome AF: 0.0983

GnomAD4 exome AF: 0.0827 AC: 120176 AN: 1452922 Hom.: 5777 Cov.: 28 AF XY: 0.0833 AC XY: 60202 AN XY: 722730

African (AFR) AF: 0.109 AC: 3621 AN: 33238

American (AMR) AF: 0.107 AC: 4779 AN: 44512

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 2922 AN: 25946

East Asian (EAS) AF: 0.235 AC: 9262 AN: 39384

South Asian (SAS) AF: 0.0834 AC: 7100 AN: 85102

European-Finnish (FIN) AF: 0.0491 AC: 2617 AN: 53266

Middle Eastern (MID) AF: 0.143 AC: 816 AN: 5720

European-Non Finnish (NFE) AF: 0.0754 AC: 83387 AN: 1105756

Other (OTH) AF: 0.0945 AC: 5672 AN: 59998

GnomAD4 genome AF: 0.0916 AC: 13936 AN: 152066 Hom.: 714 Cov.: 32 AF XY: 0.0910 AC XY: 6763 AN XY: 74320

African (AFR) AF: 0.104 AC: 4326 AN: 41516

American (AMR) AF: 0.0998 AC: 1525 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 415 AN: 3470

East Asian (EAS) AF: 0.199 AC: 1031 AN: 5172

South Asian (SAS) AF: 0.0801 AC: 387 AN: 4832

European-Finnish (FIN) AF: 0.0474 AC: 503 AN: 10620

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.0810 AC: 5496 AN: 67864

Other (OTH) AF: 0.0952 AC: 201 AN: 2112

Alfa AF: 0.0867 Hom.: 2677

Bravo AF: 0.0974

Asia WGS AF: 0.144 AC: 500 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Frontotemporal dementia and/or amyotrophic lateral sclerosis 7 (2)
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.5
DANN	Benign	0.69
PhyloP100		0.61
Mutation Taster		=92/8	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: rs1044499; hg19: chr3-87299075; COSMIC: COSV55461277; COSMIC: COSV55461277;