chr2-86542306-C-T

Variant names:

• chr2-86542306-C-T
• NM_016079.4:c.52G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016079.4(CHMP3):​c.52G>A​(p.Glu18Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHMP3 NM_016079.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.89
• Publications: 0 publications found

Genes affected

CHMP3 (HGNC:29865): (charged multivesicular body protein 3) This gene encodes a protein that sorts transmembrane proteins into lysosomes/vacuoles via the multivesicular body (MVB) pathway. This protein, along with other soluble coiled-coil containing proteins, forms part of the ESCRT-III protein complex that binds to the endosomal membrane and recruits additional cofactors for protein sorting into the MVB. This protein may also co-immunoprecipitate with a member of the IFG-binding protein superfamily. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the upstream ring finger protein 103 (RNF103) gene. [provided by RefSeq, Nov 2010]

RNF103-CHMP3 (HGNC:38847): (RNF103-CHMP3 readthrough) This locus represents naturally occurring read-through transcription between the neighboring RNF103 (ring finger protein 103) and CHMP3 (charged multivesicular body protein 3) genes. The read-through transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Oct 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016079.4. 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
	CHMP3	NM_016079.4	MANE Select	c.52G>A	p.Glu18Lys	missense	Exon 2 of 6	NP_057163.1	Q9Y3E7-1
	RNF103-CHMP3	NM_001198954.1		c.139G>A	p.Glu47Lys	missense	Exon 4 of 8	NP_001185883.1	Q9Y3E7-3
	CHMP3	NM_001193517.2		c.52G>A	p.Glu18Lys	missense	Exon 2 of 6	NP_001180446.1	Q9Y3E7-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHMP3	ENST00000263856.9	TSL:1 MANE Select	c.52G>A	p.Glu18Lys	missense	Exon 2 of 6	ENSP00000263856.4	Q9Y3E7-1
	RNF103-CHMP3	ENST00000604011.5	TSL:2	c.139G>A	p.Glu47Lys	missense	Exon 4 of 8	ENSP00000474823.1
	CHMP3	ENST00000953402.1		c.52G>A	p.Glu18Lys	missense	Exon 2 of 7	ENSP00000623461.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	-0.016	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.9
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.48
Sift	Benign	0.090	T
Sift4G	Benign	0.64	T
Polyphen		0.98	D
Vest4		0.64
MutPred		0.59		Gain of MoRF binding (P = 0.0116)
MVP		0.76
MPC		0.24
ClinPred		0.93	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.47
gMVP		0.47
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

hg19: chr2-86769429;