17-48071469-G-A

Position:

chr17-48071469-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The ENST00000225603.9(CBX1):c.524C>T(p.Ser175Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,612,782 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: 0.0000021 ( 0 hom. )

Consequence

CBX1
ENST00000225603.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.62

Variant links:

Genes affected

CBX1 (HGNC:1551): (chromobox 1) This gene encodes a highly conserved nonhistone protein, which is a member of the heterochromatin protein family . The protein is enriched in the heterochromatin and associated with centromeres. The protein has a single N-terminal chromodomain which can bind to histone proteins via methylated lysine residues, and a C-terminal chromo shadow-domain (CSD) which is responsible for the homodimerization and interaction with a number of chromatin-associated nonhistone proteins. The protein may play an important role in the epigenetic control of chromatin structure and gene expression. Several related pseudogenes are located on chromosomes 1, 3, and X. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

CBX1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity CBX1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22592795).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBX1	NM_001127228.2 linkuse as main transcript	c.524C>T	p.Ser175Leu	missense_variant	5/5	ENST00000225603.9	NP_001120700.1
CBX1	NM_006807.5 linkuse as main transcript	c.524C>T	p.Ser175Leu	missense_variant	5/5		NP_006798.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CBX1	ENST00000225603.9 linkuse as main transcript	c.524C>T	p.Ser175Leu	missense_variant	5/5	1	NM_001127228.2	ENSP00000225603	P1
CBX1	ENST00000393408.7 linkuse as main transcript	c.524C>T	p.Ser175Leu	missense_variant	5/5	1		ENSP00000377060	P1
CBX1	ENST00000402583.5 linkuse as main transcript			downstream_gene_variant		4		ENSP00000385413
CBX1	ENST00000581003.5 linkuse as main transcript			downstream_gene_variant		3		ENSP00000462242

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152128

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

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250464

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135370

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:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460654

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726714

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74312

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:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

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

Feb 27, 2024

The c.524C>T (p.S175L) alteration is located in exon 5 (coding exon 4) of the CBX1 gene. This alteration results from a C to T substitution at nucleotide position 524, causing the serine (S) at amino acid position 175 to be replaced by a leucine (L). 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

0.21

BayesDel_addAF

Benign

-0.038

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

0.057

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.86

.;D

M_CAP

Benign

0.0042

MetaRNN

Benign

0.23

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.4

L;L

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-2.7

D;D

REVEL

Benign

0.24

Sift

Benign

0.084

T;T

Sift4G

Benign

0.27

T;T

Polyphen

0.0020

B;B

Vest4

0.30

MVP

0.47

MPC

1.2

ClinPred

0.86

GERP RS

5.2

Varity_R

0.32

gMVP

0.26

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