Genetic Variant CHMP6:p.Met118Val (chr17-80997010-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024591.5(CHMP6):c.352A>G(p.Met118Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,296 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CHMP6
NM_024591.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.79

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP6	NM_024591.5 link	c.352A>G	p.Met118Val	missense_variant	Exon 5 of 8	ENST00000325167.9	NP_078867.2	Q96FZ7
CHMP6	XM_005257668.1 link	c.352A>G	p.Met118Val	missense_variant	Exon 5 of 7		XP_005257725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHMP6	ENST00000325167.9 link	c.352A>G	p.Met118Val	missense_variant	Exon 5 of 8	1	NM_024591.5	ENSP00000317468.5	Q96FZ7
CHMP6	ENST00000572778.5 link	c.289A>G	p.Met97Val	missense_variant	Exon 4 of 6	2		ENSP00000461098.1	I3L4A1
CHMP6	ENST00000571457.1 link	c.226A>G	p.Met76Val	missense_variant	Exon 4 of 7	3		ENSP00000461238.1	I3L4G8
CHMP6	ENST00000572525.5 link	c.94A>G	p.Met32Val	missense_variant	Exon 5 of 8	3		ENSP00000460389.1	I3L3E4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250576

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461296

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726948

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111746

Other (OTH)

AF:

0.0000166

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

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

Nov 16, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.352A>G (p.M118V) alteration is located in exon 5 (coding exon 5) of the CHMP6 gene. This alteration results from a A to G substitution at nucleotide position 352, causing the methionine (M) at amino acid position 118 to be replaced by a valine (V). 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

Benign

0.22

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

D;T;.;.

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.59

D;D;D;D

MetaSVM

Benign

-0.35

MutationAssessor

Pathogenic

3.0

.;M;.;.

PhyloP100

6.8

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.3

.;N;.;.

REVEL

Uncertain

0.46

Sift

Uncertain

0.0050

.;D;.;.

Sift4G

Uncertain

0.015

D;D;D;D

Polyphen

0.57

.;P;.;.

Vest4

0.81

MutPred

0.55

.;Loss of ubiquitination at K113 (P = 0.0598);.;.;

MVP

0.81

MPC

0.19

ClinPred

0.85

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.66

Mutation Taster

=78/22

polymorphism

(source)

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

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17-80997010-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over