19-58554197-C-G

Variant names:

• chr19-58554197-C-G
• rs1166533738
• NM_014453.4:c.16G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014453.4(CHMP2A):​c.16G>C​(p.Gly6Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHMP2A NM_014453.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.70
• Publications: 1 publications found

Genes affected

CHMP2A (HGNC:30216): (charged multivesicular body protein 2A) CHMP2A belongs to the chromatin-modifying protein/charged multivesicular body protein (CHMP) family. These proteins are components of ESCRT-III (endosomal sorting complex required for transport III), a complex involved in degradation of surface receptor proteins and formation of endocytic multivesicular bodies (MVBs). Some CHMPs have both nuclear and cytoplasmic/vesicular distributions, and one such CHMP, CHMP1A (MIM 164010), is required for both MVB formation and regulation of cell cycle progression (Tsang et al., 2006 [PubMed 16730941]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014453.4. 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
	CHMP2A	NM_014453.4	MANE Select	c.16G>C	p.Gly6Arg	missense	Exon 2 of 6	NP_055268.1	O43633
	CHMP2A	NM_198426.3		c.16G>C	p.Gly6Arg	missense	Exon 2 of 6	NP_940818.1	O43633

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHMP2A	ENST00000312547.7	TSL:1 MANE Select	c.16G>C	p.Gly6Arg	missense	Exon 2 of 6	ENSP00000310440.1	O43633
	CHMP2A	ENST00000600118.6	TSL:1	c.16G>C	p.Gly6Arg	missense	Exon 2 of 6	ENSP00000469240.1	O43633
	CHMP2A	ENST00000601220.5	TSL:1	c.16G>C	p.Gly6Arg	missense	Exon 2 of 6	ENSP00000472680.1	O43633

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		6.7
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.52
MutPred		0.37		Gain of MoRF binding (P = 0.0052)
MVP		0.83
MPC		1.5
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.70
gMVP		0.98
Mutation Taster		=0/100	disease causing

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: rs1166533738; hg19: chr19-59065564;