3-87227372-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 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:2
• Conservation: PhyloP100: 0.546

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]

ACMG classification

Verdict is Benign. Variant got -20 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 [Likely_benign]. Clinvar id is 346801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-87227372-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0102 (1557/152280) while in subpopulation NFE AF= 0.015 (1021/68022). AF 95% confidence interval is 0.0142. There are 10 homozygotes in gnomad4. There are 700 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1557 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHMP2B	NM_014043.4	c.-151C>A		5_prime_UTR_variant	1/6	ENST00000263780.9
CHMP2B	NM_001244644.2	c.-182C>A		5_prime_UTR_variant	1/5
CHMP2B	NM_001410777.1	c.-182C>A		5_prime_UTR_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHMP2B	ENST00000263780.9	c.-151C>A		5_prime_UTR_variant	1/6	1	NM_014043.4	P1

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

Gnomad4 AFR exome AF: 0.00278

Gnomad4 AMR exome AF: 0.00962

Gnomad4 ASJ exome AF: 0.0204

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00867

Gnomad4 FIN exome AF: 0.00680

Gnomad4 NFE exome AF: 0.0152

Gnomad4 OTH exome AF: 0.0133

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

Gnomad4 AFR AF: 0.00277

Gnomad4 AMR AF: 0.0148

Gnomad4 ASJ AF: 0.0205

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00560

Gnomad4 FIN AF: 0.00499

Gnomad4 NFE AF: 0.0150

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0129 Hom.: 3

Bravo AF: 0.0109

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	12
Dann	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs77328592; hg19: chr3-87276522;