19-58554057-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_014453.4(CHMP2A):​c.156G>C​(p.Lys52Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

CHMP2A
NM_014453.4 missense

Scores

8
6
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.424
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHMP2ANM_014453.4 linkc.156G>C p.Lys52Asn missense_variant Exon 2 of 6 ENST00000312547.7 NP_055268.1 O43633A0A024R4S0
CHMP2ANM_198426.3 linkc.156G>C p.Lys52Asn missense_variant Exon 2 of 6 NP_940818.1 O43633A0A024R4S0
CHMP2AXM_005258746.3 linkc.156G>C p.Lys52Asn missense_variant Exon 2 of 5 XP_005258803.1 M0R1T5
CHMP2AXM_005258747.4 linkc.156G>C p.Lys52Asn missense_variant Exon 2 of 5 XP_005258804.1 M0R1T5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHMP2AENST00000312547.7 linkc.156G>C p.Lys52Asn missense_variant Exon 2 of 6 1 NM_014453.4 ENSP00000310440.1 O43633

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152246
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000438
AC:
11
AN:
251266
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135826
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000466
Gnomad NFE exome
AF:
0.0000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1461512
Hom.:
0
Cov.:
30
AF XY:
0.0000110
AC XY:
8
AN XY:
727078
show subpopulations
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:
0.0000188
Gnomad4 NFE exome
AF:
0.0000171
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152246
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74374
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000906
AC:
11
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 10, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.156G>C (p.K52N) alteration is located in exon 2 (coding exon 1) of the CHMP2A gene. This alteration results from a G to C substitution at nucleotide position 156, causing the lysine (K) at amino acid position 52 to be replaced by an asparagine (N). 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
0.94
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.80
D;D;D;D;D
Eigen
Benign
0.16
Eigen_PC
Benign
0.027
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Pathogenic
0.98
.;.;D;D;D
M_CAP
Pathogenic
0.32
D
MetaRNN
Pathogenic
0.82
D;D;D;D;D
MetaSVM
Uncertain
-0.013
T
MutationAssessor
Pathogenic
3.5
M;M;M;.;.
PrimateAI
Pathogenic
0.80
D
PROVEAN
Pathogenic
-4.9
.;.;D;.;.
REVEL
Uncertain
0.58
Sift
Uncertain
0.0010
.;.;D;.;.
Sift4G
Uncertain
0.0030
D;D;D;.;.
Polyphen
0.94
P;P;P;.;.
Vest4
0.57
MutPred
0.70
Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);
MVP
0.82
MPC
1.2
ClinPred
0.95
D
GERP RS
-1.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.82
gMVP
0.99

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs548744646; hg19: chr19-59065424; API