Variant 17-80994653-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024591.5(CHMP6):c.136G>A(p.Ala46Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,582,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

CHMP6
NM_024591.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.89

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16681841).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHMP6	NM_024591.5 linkuse as main transcript	c.136G>A	p.Ala46Thr	missense_variant	2/8	ENST00000325167.9
CHMP6	XM_005257668.1 linkuse as main transcript	c.136G>A	p.Ala46Thr	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CHMP6	ENST00000325167.9 linkuse as main transcript	c.136G>A	p.Ala46Thr	missense_variant	2/8	1	NM_024591.5	P1
CHMP6	ENST00000572778.5 linkuse as main transcript	c.73G>A	p.Ala25Thr	missense_variant	1/6	2
CHMP6	ENST00000571457.1 linkuse as main transcript	c.10G>A	p.Ala4Thr	missense_variant	1/7	3
CHMP6	ENST00000572525.5 linkuse as main transcript	c.-123G>A		5_prime_UTR_variant	2/8	3

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152162

Hom.:

Cov.:

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000639

AC:

AN:

187790

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

102014

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000367

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000800

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000878

Gnomad OTH exome

AF:

0.000418

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1430412

Hom.:

Cov.:

AF XY:

0.0000395

AC XY:

AN XY:

708516

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000512

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000613

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000291

Gnomad4 OTH exome

AF:

0.0000506

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74326

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000112

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000424

AC:

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

Mar 07, 2024

The c.136G>A (p.A46T) alteration is located in exon 2 (coding exon 2) of the CHMP6 gene. This alteration results from a G to A substitution at nucleotide position 136, causing the alanine (A) at amino acid position 46 to be replaced by a threonine (T). 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

0.066

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;.;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.059

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.5

L;.;.

MutationTaster

Benign

0.96

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.66

N;.;.

REVEL

Benign

0.15

Sift

Benign

0.34

T;.;.

Sift4G

Benign

0.42

T;T;T

Polyphen

0.28

B;.;.

Vest4

0.31

MutPred

0.50

Gain of phosphorylation at A46 (P = 0.0103);.;.;

MVP

0.43

MPC

0.065

ClinPred

0.070

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.061

gMVP

0.058

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.

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