19-58551674-C-T

Variant names:

• chr19-58551674-C-T
• NM_014453.4:c.644G>A

Variant summary

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

The NM_014453.4(CHMP2A):​c.644G>A​(p.Arg215Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,748 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHMP2A NM_014453.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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=0.36486042).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP2A	NM_014453.4	c.644G>A	p.Arg215Gln	missense_variant	Exon 6 of 6	ENST00000312547.7	NP_055268.1
CHMP2A	NM_198426.3	c.644G>A	p.Arg215Gln	missense_variant	Exon 6 of 6		NP_940818.1
CHMP2A	XM_005258746.3	c.773G>A	p.Arg258Gln	missense_variant	Exon 5 of 5		XP_005258803.1
CHMP2A	XM_005258747.4	c.773G>A	p.Arg258Gln	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.644G>A	p.Arg215Gln	missense_variant	Exon 6 of 6	1	NM_014453.4	ENSP00000310440.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461748 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727168

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.644G>A (p.R215Q) alteration is located in exon 6 (coding exon 5) of the CHMP2A gene. This alteration results from a G to A substitution at nucleotide position 644, causing the arginine (R) at amino acid position 215 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.018
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	.;.;D
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.4	M;M;M
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.5	.;.;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	.;.;D
Sift4G	Benign	0.12	T;T;T
Polyphen		0.24	B;B;B
Vest4		0.69
MutPred		0.56		Loss of MoRF binding (P = 0.041);Loss of MoRF binding (P = 0.041);Loss of MoRF binding (P = 0.041);
MVP		0.79
MPC		0.55
ClinPred		0.98	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.55
gMVP		0.46

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-59063041; COSMIC: COSV53396598; COSMIC: COSV53396598;