rs77328592

Variant names:

• chr3-87227372-C-A
• rs77328592
• NM_014043.4:c.-151C>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014043.4(CHMP2B):​c.-151C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 786,944 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (10 hom., cov: 32)
  • Exomes 𝑓: 0.013 (65 hom.)
• Consequence: CHMP2B NM_014043.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.546
• Publications: 2 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-87227372-C-A is Benign according to our data. Variant chr3-87227372-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 346801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1557 AD gene.

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.-151C>A		5_prime_UTR	Exon 1 of 6	NP_054762.2
	CHMP2B	NM_001410777.1		c.-182C>A		5_prime_UTR	Exon 1 of 7	NP_001397706.1
	CHMP2B	NM_001244644.2		c.-182C>A		5_prime_UTR	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.-151C>A		5_prime_UTR	Exon 1 of 6	ENSP00000263780.4	Q9UQN3-1
	CHMP2B	ENST00000472024.3	TSL:5	c.-234C>A		5_prime_UTR	Exon 1 of 7	ENSP00000480032.2	A0A087WW88
	CHMP2B	ENST00000676705.1		c.-230C>A		5_prime_UTR	Exon 1 of 7	ENSP00000504098.1	A0A087WW88

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1557 AN: 152162 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.0126 AC: 7982 AN: 634664 Hom.: 65 Cov.: 8 AF XY: 0.0128 AC XY: 4308 AN XY: 337360

African (AFR) AF: 0.00278 AC: 48 AN: 17236

American (AMR) AF: 0.00962 AC: 314 AN: 32630

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 381 AN: 18664

East Asian (EAS) AF: 0.00 AC: 0 AN: 33508

South Asian (SAS) AF: 0.00867 AC: 552 AN: 63656

European-Finnish (FIN) AF: 0.00680 AC: 295 AN: 43354

Middle Eastern (MID) AF: 0.0141 AC: 54 AN: 3818

European-Non Finnish (NFE) AF: 0.0152 AC: 5902 AN: 389124

Other (OTH) AF: 0.0133 AC: 436 AN: 32674

GnomAD4 genome AF: 0.0102 AC: 1557 AN: 152280 Hom.: 10 Cov.: 32 AF XY: 0.00940 AC XY: 700 AN XY: 74440

African (AFR) AF: 0.00277 AC: 115 AN: 41560

American (AMR) AF: 0.0148 AC: 226 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 71 AN: 3468

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5160

South Asian (SAS) AF: 0.00560 AC: 27 AN: 4824

European-Finnish (FIN) AF: 0.00499 AC: 53 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0150 AC: 1021 AN: 68022

Other (OTH) AF: 0.0137 AC: 29 AN: 2112

Alfa AF: 0.0135 Hom.: 18

Bravo AF: 0.0109

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Frontotemporal dementia and/or amyotrophic lateral sclerosis 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	12
DANN	Benign	0.92
PhyloP100		0.55
PromoterAI		-0.068	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=299/1	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: rs77328592; hg19: chr3-87276522;