chr19-58551674-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36486042).

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.644G>A	p.Arg215Gln	missense	Exon 6 of 6	NP_055268.1	O43633
	CHMP2A	NM_198426.3		c.644G>A	p.Arg215Gln	missense	Exon 6 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.644G>A	p.Arg215Gln	missense	Exon 6 of 6	ENSP00000310440.1	O43633
	CHMP2A	ENST00000600118.6	TSL:1	c.644G>A	p.Arg215Gln	missense	Exon 6 of 6	ENSP00000469240.1	O43633
	CHMP2A	ENST00000601220.5	TSL:1	c.644G>A	p.Arg215Gln	missense	Exon 6 of 6	ENSP00000472680.1	O43633

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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	0.89
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	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
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.12	T
Polyphen		0.24	B
Vest4		0.69
MutPred		0.56		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
Mutation Taster		=68/32	polymorphism

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

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