Variant chr17-80995672-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_024591.5(CHMP6):c.262G>A(p.Val88Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CHMP6
NM_024591.5 missense, splice_region

Scores

Splicing: ADA: 0.2867

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.56

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 made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3669762).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHMP6	NM_024591.5 linkuse as main transcript	c.262G>A	p.Val88Ile	missense_variant, splice_region_variant	4/8	ENST00000325167.9	NP_078867.2	Q96FZ7
CHMP6	XM_005257668.1 linkuse as main transcript	c.262G>A	p.Val88Ile	missense_variant, splice_region_variant	4/7		XP_005257725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CHMP6	ENST00000325167.9 linkuse as main transcript	c.262G>A	p.Val88Ile	missense_variant, splice_region_variant	4/8	1	NM_024591.5	ENSP00000317468.5	Q96FZ7
CHMP6	ENST00000572778.5 linkuse as main transcript	c.199G>A	p.Val67Ile	missense_variant, splice_region_variant	3/6	2		ENSP00000461098.1	I3L4A1
CHMP6	ENST00000571457.1 linkuse as main transcript	c.136G>A	p.Val46Ile	missense_variant, splice_region_variant	3/7	3		ENSP00000461238.1	I3L4G8
CHMP6	ENST00000572525.5 linkuse as main transcript	c.4G>A	p.Val2Ile	missense_variant, splice_region_variant	4/8	3		ENSP00000460389.1	I3L3E4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152248

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461600

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74388

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

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 08, 2024

The c.262G>A (p.V88I) alteration is located in exon 4 (coding exon 4) of the CHMP6 gene. This alteration results from a G to A substitution at nucleotide position 262, causing the valine (V) at amino acid position 88 to be replaced by an isoleucine (I). 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

0.14

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;T;.;.

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.76

T;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.37

T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Benign

1.7

.;L;.;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.94

.;N;.;.

REVEL

Benign

0.28

Sift

Benign

0.11

.;T;.;.

Sift4G

Benign

0.14

T;T;T;T

Polyphen

0.55

.;P;.;.

Vest4

0.64

MutPred

0.49

.;Gain of disorder (P = 0.1887);.;.;

MVP

0.40

MPC

0.12

ClinPred

0.84

GERP RS

4.4

Varity_R

0.16

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.29

dbscSNV1_RF

Benign

0.43

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