dbSNP rs757131739: CHMP6:p.Arg12Pro (chr17-80991953-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_024591.5(CHMP6):c.35G>C(p.Arg12Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000477 in 1,466,428 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000046 ( 0 hom. )

Consequence

CHMP6
NM_024591.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.86

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29877207).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP6	NM_024591.5 link	c.35G>C	p.Arg12Pro	missense_variant	Exon 1 of 8	ENST00000325167.9	NP_078867.2	Q96FZ7
CHMP6	XM_005257668.1 link	c.35G>C	p.Arg12Pro	missense_variant	Exon 1 of 7		XP_005257725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP6	ENST00000325167.9 link	c.35G>C	p.Arg12Pro	missense_variant	Exon 1 of 8	1	NM_024591.5	ENSP00000317468.5		Q96FZ7
CHMP6	ENST00000572525.5 link	c.-196+280G>C		intron_variant	Intron 1 of 7	3		ENSP00000460389.1		I3L3E4

Frequencies

GnomAD3 genomes

AF:

0.00000662

AC:

AN:

151146

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000937

AC:

AN:

106754

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:

0.0000254

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000456

AC:

AN:

1315282

Hom.:

Cov.:

AF XY:

0.00000308

AC XY:

AN XY:

650046

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26648

American (AMR)

AF:

0.00

AC:

AN:

28844

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22112

East Asian (EAS)

AF:

0.00

AC:

AN:

28014

South Asian (SAS)

AF:

0.00

AC:

AN:

73344

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43840

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4546

European-Non Finnish (NFE)

AF:

0.00000483

AC:

AN:

1035094

Other (OTH)

AF:

0.0000189

AC:

AN:

52840

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000662

AC:

AN:

151146

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73816

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41330

American (AMR)

AF:

0.00

AC:

AN:

15202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10214

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67638

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000936

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 01, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.35G>C (p.R12P) alteration is located in exon 1 (coding exon 1) of the CHMP6 gene. This alteration results from a G to C substitution at nucleotide position 35, causing the arginine (R) at amino acid position 12 to be replaced by a proline (P). 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

Pathogenic

0.58

BayesDel_addAF

Uncertain

0.012

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Benign

-0.095

Eigen_PC

Benign

-0.054

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.30

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.6

PhyloP100

3.9

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.25

Sift

Benign

0.083

Sift4G

Benign

0.14

Polyphen

0.20

Vest4

0.35

MutPred

0.45

Loss of MoRF binding (P = 0.003);

MVP

0.55

MPC

0.46

ClinPred

0.93

GERP RS

1.7

PromoterAI

-0.17

Neutral

(source)

Varity_R

0.96

gMVP

0.39

Mutation Taster

=56/44

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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rs757131739

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over