chr3-87227421-C-T

Variant names:

• chr3-87227421-C-T
• rs36098294
• NM_014043.4:c.-102C>T

Variant summary

Our verdict is Benign. The variant received -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 premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0420
• Publications: 3 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 -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 Benign/Likely_benign. ClinVar VariationId is 346802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1450 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.-102C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_054762.2
	CHMP2B	NM_014043.4	MANE Select	c.-102C>T		5_prime_UTR	Exon 1 of 6	NP_054762.2
	CHMP2B	NM_001410777.1		c.-133C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001397706.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHMP2B	ENST00000263780.9	TSL:1 MANE Select	c.-102C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000263780.4	Q9UQN3-1
	CHMP2B	ENST00000263780.9	TSL:1 MANE Select	c.-102C>T		5_prime_UTR	Exon 1 of 6	ENSP00000263780.4	Q9UQN3-1
	CHMP2B	ENST00000472024.3	TSL:5	c.-185C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000480032.2	A0A087WW88

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

African (AFR) AF: 0.00164 AC: 48 AN: 29242

American (AMR) AF: 0.00443 AC: 194 AN: 43768

Ashkenazi Jewish (ASJ) AF: 0.00478 AC: 118 AN: 24688

East Asian (EAS) AF: 0.00 AC: 0 AN: 38546

South Asian (SAS) AF: 0.00209 AC: 171 AN: 81750

European-Finnish (FIN) AF: 0.0189 AC: 993 AN: 52440

Middle Eastern (MID) AF: 0.000932 AC: 5 AN: 5364

European-Non Finnish (NFE) AF: 0.0148 AC: 13639 AN: 924130

Other (OTH) AF: 0.00980 AC: 523 AN: 53350

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

African (AFR) AF: 0.00224 AC: 93 AN: 41588

American (AMR) AF: 0.00470 AC: 72 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.0155 AC: 165 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0158 AC: 1078 AN: 68024

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00639 Hom.: 3

Bravo AF: 0.00804

Asia WGS AF: 0.00173 AC: 6 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	-0.98
CADD	Benign	9.0
DANN	Benign	0.88
PhyloP100		0.042
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=300/0	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: rs36098294; hg19: chr3-87276571; COSMIC: COSV55461752; COSMIC: COSV55461752;