3-87227318-C-T

Variant names:

• chr3-87227318-C-T
• rs556556377
• NM_014043.4:c.-205C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_014043.4(CHMP2B):​c.-205C>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 0.0000194 in 617,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: CHMP2B NM_014043.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BS2: High AC in GnomAdExome4 at 9 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.-205C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	NP_054762.2
	CHMP2B	NM_014043.4	MANE Select	c.-205C>T		5_prime_UTR	Exon 1 of 6	NP_054762.2
	CHMP2B	NM_001410777.1		c.-236C>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.-205C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000263780.4	Q9UQN3-1
	CHMP2B	ENST00000263780.9	TSL:1 MANE Select	c.-205C>T		5_prime_UTR	Exon 1 of 6	ENSP00000263780.4	Q9UQN3-1
	CHMP2B	ENST00000472024.3	TSL:5	c.-288C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000480032.2	A0A087WW88

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000193 AC: 9 AN: 465280 Hom.: 0 Cov.: 4 AF XY: 0.0000122 AC XY: 3 AN XY: 246754

African (AFR) AF: 0.00 AC: 0 AN: 12762

American (AMR) AF: 0.000196 AC: 4 AN: 20368

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14116

East Asian (EAS) AF: 0.00 AC: 0 AN: 31304

South Asian (SAS) AF: 0.00 AC: 0 AN: 48064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32042

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2332

European-Non Finnish (NFE) AF: 0.0000144 AC: 4 AN: 277760

Other (OTH) AF: 0.0000377 AC: 1 AN: 26532

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Frontotemporal dementia and/or amyotrophic lateral sclerosis 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	18
DANN	Benign	0.94
PhyloP100		1.1
PromoterAI		0.24	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs556556377; hg19: chr3-87276468;