Genetic Variant CHMP6:p.Asn79Thr (chr17-80995081-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024591.5(CHMP6):c.236A>C(p.Asn79Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CHMP6
NM_024591.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.17

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14867294).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP6	NM_024591.5 link	c.236A>C	p.Asn79Thr	missense_variant	Exon 3 of 8	ENST00000325167.9	NP_078867.2	Q96FZ7
CHMP6	XM_005257668.1 link	c.236A>C	p.Asn79Thr	missense_variant	Exon 3 of 7		XP_005257725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHMP6	ENST00000325167.9 link	c.236A>C	p.Asn79Thr	missense_variant	Exon 3 of 8	1	NM_024591.5	ENSP00000317468.5	Q96FZ7
CHMP6	ENST00000572778.5 link	c.173A>C	p.Asn58Thr	missense_variant	Exon 2 of 6	2		ENSP00000461098.1	I3L4A1
CHMP6	ENST00000571457.1 link	c.110A>C	p.Asn37Thr	missense_variant	Exon 2 of 7	3		ENSP00000461238.1	I3L4G8
CHMP6	ENST00000572525.5 link	c.-23A>C		5_prime_UTR_variant	Exon 3 of 8	3		ENSP00000460389.1	I3L3E4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

229260

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1450432

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720272

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33444

American (AMR)

AF:

0.00

AC:

AN:

42608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25720

East Asian (EAS)

AF:

0.00

AC:

AN:

39206

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83640

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51738

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108288

Other (OTH)

AF:

0.00

AC:

AN:

60038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.236A>C (p.N79T) alteration is located in exon 3 (coding exon 3) of the CHMP6 gene. This alteration results from a A to C substitution at nucleotide position 236, causing the asparagine (N) at amino acid position 79 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

0.087

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.23

T;.;.

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.77

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.76

T;T;T

M_CAP

Benign

0.044

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;.;.

PhyloP100

1.2

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.5

N;.;.

REVEL

Benign

0.11

Sift

Benign

0.55

T;.;.

Sift4G

Benign

0.46

T;T;T

Polyphen

0.098

B;.;.

Vest4

0.31

MutPred

0.39

Gain of phosphorylation at N79 (P = 0.0424);.;.;

MVP

0.57

MPC

0.068

ClinPred

0.12

GERP RS

-0.80

PromoterAI

-0.036

Neutral

(source)

Varity_R

0.16

gMVP

0.35

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over