chr19-58551759-C-T

Variant names:

• chr19-58551759-C-T
• rs149478183
• NM_014453.4:c.559G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014453.4(CHMP2A):​c.559G>A​(p.Gly187Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G187R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHMP2A NM_014453.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.39

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27958524).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP2A	NM_014453.4	c.559G>A	p.Gly187Ser	missense_variant	Exon 6 of 6	ENST00000312547.7	NP_055268.1
CHMP2A	NM_198426.3	c.559G>A	p.Gly187Ser	missense_variant	Exon 6 of 6		NP_940818.1
CHMP2A	XM_005258746.3	c.688G>A	p.Gly230Ser	missense_variant	Exon 5 of 5		XP_005258803.1
CHMP2A	XM_005258747.4	c.688G>A	p.Gly230Ser	missense_variant	Exon 5 of 5		XP_005258804.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP2A	ENST00000312547.7	c.559G>A	p.Gly187Ser	missense_variant	Exon 6 of 6	1	NM_014453.4	ENSP00000310440.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Benign	0.89
DEOGEN2	Benign	0.057	T;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.022
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;.;D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.4	L;L;L
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.9	.;.;N
REVEL	Uncertain	0.34
Sift	Benign	0.34	.;.;T
Sift4G	Benign	0.75	T;T;T
Polyphen		0.044	B;B;B
Vest4		0.40
MutPred		0.44		Gain of phosphorylation at G187 (P = 0.023);Gain of phosphorylation at G187 (P = 0.023);Gain of phosphorylation at G187 (P = 0.023);
MVP		0.71
MPC		0.59
ClinPred		0.87	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.67

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: rs149478183; hg19: chr19-59063126;