Variant 17-79795357-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_020649.3(CBX8):c.448C>T(p.Arg150Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000628 in 1,591,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R150Q) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

CBX8
NM_020649.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.312

Variant links:

Genes affected

CBX8 (HGNC:15962): (chromobox 8) Enables methylated histone binding activity. Involved in negative regulation of transcription by RNA polymerase II. Located in chromatin and nucleoplasm. Part of PRC1 complex. Biomarker of esophagus squamous cell carcinoma and glioblastoma. [provided by Alliance of Genome Resources, Apr 2022]

CBX8 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22949761).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBX8	NM_020649.3 linkuse as main transcript	c.448C>T	p.Arg150Trp	missense_variant	5/5	ENST00000269385.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CBX8	ENST00000269385.9 linkuse as main transcript	c.448C>T	p.Arg150Trp	missense_variant	5/5	1	NM_020649.3	P1
CBX8	ENST00000413392.5 linkuse as main transcript	c.418C>T	p.Arg140Trp	missense_variant	5/5	3
CBX8	ENST00000427800.2 linkuse as main transcript	c.373C>T	p.Arg125Trp	missense_variant	5/5	2
CBX8	ENST00000485449.1 linkuse as main transcript			downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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

GnomAD3 exomes

AF:

0.00000942

AC:

AN:

212238

Hom.:

AF XY:

0.0000175

AC XY:

AN XY:

114032

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000212

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000486

AC:

AN:

1439368

Hom.:

Cov.:

AF XY:

0.00000980

AC XY:

AN XY:

714086

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

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:

0.00000454

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

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

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 24, 2023

The c.448C>T (p.R150W) alteration is located in exon 5 (coding exon 5) of the CBX8 gene. This alteration results from a C to T substitution at nucleotide position 448, causing the arginine (R) at amino acid position 150 to be replaced by a tryptophan (W). 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

0.19

BayesDel_addAF

Benign

-0.0038

BayesDel_noAF

Benign

-0.24

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.15

T;.;T

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.75

T;T;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

1.1

L;.;.

MutationTaster

Benign

0.82

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.23

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.020

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.13

MutPred

0.17

Gain of MoRF binding (P = 0.0687);.;.;

MVP

0.39

MPC

0.22

ClinPred

0.58

GERP RS

3.5

Varity_R

0.080

gMVP

0.28

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