Variant 17-80995020-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024591.5(CHMP6):c.175C>T(p.Arg59Trp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000201 in 1,591,860 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

CHMP6
NM_024591.5 missense, splice_region

Scores

Splicing: ADA: 0.004069

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.61

Variant links:

Genes affected

CHMP6 (HGNC:25675): (charged multivesicular body protein 6) This gene encodes a member of the chromatin-modifying protein/charged multivesicular body protein family. Proteins in this family are part of the ESCRT-III (endosomal sorting complex required for transport III) which degrades surface receptors, and in biosynthesis of endosomes. [provided by RefSeq, Mar 2012]

CHMP6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHMP6	NM_024591.5 linkuse as main transcript	c.175C>T	p.Arg59Trp	missense_variant, splice_region_variant	3/8	ENST00000325167.9
CHMP6	XM_005257668.1 linkuse as main transcript	c.175C>T	p.Arg59Trp	missense_variant, splice_region_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CHMP6	ENST00000325167.9 linkuse as main transcript	c.175C>T	p.Arg59Trp	missense_variant, splice_region_variant	3/8	1	NM_024591.5	P1
CHMP6	ENST00000572778.5 linkuse as main transcript	c.112C>T	p.Arg38Trp	missense_variant, splice_region_variant	2/6	2
CHMP6	ENST00000571457.1 linkuse as main transcript	c.49C>T	p.Arg17Trp	missense_variant, splice_region_variant	2/7	3
CHMP6	ENST00000572525.5 linkuse as main transcript	c.-84C>T		splice_region_variant, 5_prime_UTR_variant	3/8	3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000480

GnomAD3 exomes

AF:

0.0000140

AC:

AN:

214882

Hom.:

AF XY:

0.0000173

AC XY:

AN XY:

115374

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000343

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000381

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000103

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000201

AC:

AN:

1439766

Hom.:

Cov.:

AF XY:

0.0000210

AC XY:

AN XY:

713738

show subpopulations

Gnomad4 AFR exome

AF:

0.0000601

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000180

Gnomad4 SAS exome

AF:

0.0000243

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000136

Gnomad4 OTH exome

AF:

0.0000502

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

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:

0.000480

Bravo

AF:

0.0000264

ExAC

AF:

0.00000834

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2022

The c.175C>T (p.R59W) alteration is located in exon 3 (coding exon 3) of the CHMP6 gene. This alteration results from a C to T substitution at nucleotide position 175, causing the arginine (R) at amino acid position 59 to be replaced by a tryptophan (W). 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

Uncertain

0.48

BayesDel_addAF

Benign

-0.025

BayesDel_noAF

Benign

-0.16

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.76

D;.;.

Eigen

Benign

0.089

Eigen_PC

Benign

0.079

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Uncertain

0.58

D;D;D

MetaSVM

Uncertain

-0.20

MutationAssessor

Uncertain

2.6

M;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-6.4

D;.;.

REVEL

Uncertain

0.41

Sift

Uncertain

0.029

D;.;.

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

0.24

B;.;.

Vest4

0.55

MutPred

0.57

Gain of helix (P = 0.0696);.;.;

MVP

0.58

MPC

0.070

ClinPred

0.82

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0041

dbscSNV1_RF

Benign

0.028

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over