3-87227421-C-T

Position:

• chr3-87227421-C-T

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.-102C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,405,614 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (11 hom., cov: 32)
  • Exomes 𝑓: 0.013 (140 hom.)
• Consequence: CHMP2B NM_014043.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0420

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=-0.98).
• BP6: Variant 3-87227421-C-T is Benign according to our data. Variant chr3-87227421-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 346802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-87227421-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00952 (1450/152336) while in subpopulation NFE AF= 0.0158 (1078/68024). AF 95% confidence interval is 0.0151. There are 11 homozygotes in gnomad4. There are 679 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1450 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHMP2B	NM_014043.4	c.-102C>T		5_prime_UTR_variant	1/6	ENST00000263780.9	NP_054762.2
CHMP2B	NM_001244644.2	c.-133C>T		5_prime_UTR_variant	1/5		NP_001231573.1
CHMP2B	NM_001410777.1	c.-133C>T		5_prime_UTR_variant	1/7		NP_001397706.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHMP2B	ENST00000263780.9	c.-102C>T		5_prime_UTR_variant	1/6	1	NM_014043.4	ENSP00000263780	P1

Frequencies

GnomAD3 genomes AF: 0.00953 AC: 1450 AN: 152220 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0155

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0158

Gnomad OTH AF: 0.00813

GnomAD4 exome AF: 0.0125 AC: 15691 AN: 1253278 Hom.: 140 Cov.: 18 AF XY: 0.0123 AC XY: 7773 AN XY: 633156

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.00443

Gnomad4 ASJ exome AF: 0.00478

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00209

Gnomad4 FIN exome AF: 0.0189

Gnomad4 NFE exome AF: 0.0148

Gnomad4 OTH exome AF: 0.00980

GnomAD4 genome AF: 0.00952 AC: 1450 AN: 152336 Hom.: 11 Cov.: 32 AF XY: 0.00912 AC XY: 679 AN XY: 74488

Gnomad4 AFR AF: 0.00224

Gnomad4 AMR AF: 0.00470

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0155

Gnomad4 NFE AF: 0.0158

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00639 Hom.: 3

Bravo AF: 0.00804

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	9.0
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

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: rs36098294; hg19: chr3-87276571; COSMIC: COSV55461752; COSMIC: COSV55461752;