Genetic Variant NM_024591.5:c.452A>G (chr17-80997298-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.452A>G(p.Glu151Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,611,242 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E151V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

CHMP6
NM_024591.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.79

Publications

0 publications found

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:

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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.452A>G	p.Glu151Gly	missense_variant	Exon 6 of 8	ENST00000325167.9	NP_078867.2	Q96FZ7
CHMP6	XM_005257668.1 link	c.452A>G	p.Glu151Gly	missense_variant	Exon 6 of 7		XP_005257725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHMP6	ENST00000325167.9 link	c.452A>G	p.Glu151Gly	missense_variant	Exon 6 of 8	1	NM_024591.5	ENSP00000317468.5	Q96FZ7
CHMP6	ENST00000572778.5 link	c.389A>G	p.Glu130Gly	missense_variant	Exon 5 of 6	2		ENSP00000461098.1	I3L4A1
CHMP6	ENST00000571457.1 link	c.326A>G	p.Glu109Gly	missense_variant	Exon 5 of 7	3		ENSP00000461238.1	I3L4G8
CHMP6	ENST00000572525.5 link	c.194A>G	p.Glu65Gly	missense_variant	Exon 6 of 8	3		ENSP00000460389.1	I3L3E4

Frequencies

GnomAD3 genomes

AF:

0.0000199

AC:

AN:

150716

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000298

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000810

AC:

AN:

246960

AF XY:

0.0000150

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:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1460526

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726592

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53142

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1111138

Other (OTH)

AF:

0.0000166

AC:

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000199

AC:

AN:

150716

Hom.:

Cov.:

AF XY:

0.0000272

AC XY:

AN XY:

73628

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41264

American (AMR)

AF:

0.00

AC:

AN:

15020

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3416

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4760

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000298

AC:

AN:

67208

Other (OTH)

AF:

0.00

AC:

AN:

2060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000434

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.48

T;D;.;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Uncertain

0.60

D;D;D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.7

.;M;.;.

PhyloP100

8.8

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.8

.;D;.;.

REVEL

Uncertain

0.56

Sift

Uncertain

0.014

.;D;.;.

Sift4G

Uncertain

0.0070

D;T;T;D

Polyphen

0.86

.;P;.;.

Vest4

0.78

MutPred

0.41

.;Loss of solvent accessibility (P = 0.0187);.;.;

MVP

0.56

MPC

0.42

ClinPred

0.98

GERP RS

4.3

Varity_R

0.62

gMVP

0.74

Mutation Taster

=45/55

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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NM_024591.5:c.452A>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over