rs1206311342

Variant names:

• chr19-58552268-C-G
• rs1206311342
• NM_014453.4:c.339G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-58552268-C-G
• chr19-58552268-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014453.4(CHMP2A):​c.339G>C​(p.Met113Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHMP2A NM_014453.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.83

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP2A	NM_014453.4	c.339G>C	p.Met113Ile	missense_variant	Exon 3 of 6	ENST00000312547.7	NP_055268.1
CHMP2A	NM_198426.3	c.339G>C	p.Met113Ile	missense_variant	Exon 3 of 6		NP_940818.1
CHMP2A	XM_005258746.3	c.339G>C	p.Met113Ile	missense_variant	Exon 3 of 5		XP_005258803.1
CHMP2A	XM_005258747.4	c.339G>C	p.Met113Ile	missense_variant	Exon 3 of 5		XP_005258804.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP2A	ENST00000312547.7	c.339G>C	p.Met113Ile	missense_variant	Exon 3 of 6	1	NM_014453.4	ENSP00000310440.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251418 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;D;D;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	.;.;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	3.3	M;M;M;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.0	.;.;D;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	.;.;D;.
Sift4G	Uncertain	0.0050	D;D;D;.
Polyphen		0.77	P;P;P;.
Vest4		0.77
MutPred		0.72		Gain of catalytic residue at M113 (P = 0.0125);Gain of catalytic residue at M113 (P = 0.0125);Gain of catalytic residue at M113 (P = 0.0125);Gain of catalytic residue at M113 (P = 0.0125);
MVP		0.82
MPC		1.1
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.95

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: rs1206311342; hg19: chr19-59063635;