Genetic Variant CBX2:p.Arg23Arg (chr17-79778304-C-A) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_005189.3(CBX2):c.69C>A(p.Arg23Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,558,110 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 7 hom. )

Consequence

CBX2
NM_005189.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.128

Variant links:

Genes affected

CBX2 (HGNC:1552): (chromobox 2) This gene encodes a component of the polycomb multiprotein complex, which is required to maintain the transcriptionally repressive state of many genes throughout development via chromatin remodeling and modification of histones. Disruption of this gene in mice results in male-to-female gonadal sex reversal. Mutations in this gene are also associated with gonadal dysgenesis in humans. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Mar 2010]

CBX2 links:

ENSG00000295072 (HGNC:):

ENSG00000295072 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 17-79778304-C-A is Benign according to our data. Variant chr17-79778304-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2069107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-79778304-C-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.128 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 7 AR,SD,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBX2	NM_005189.3 link	c.69C>A	p.Arg23Arg	synonymous_variant	Exon 1 of 5	ENST00000310942.9	NP_005180.1	Q14781-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CBX2	ENST00000310942.9 link	c.69C>A	p.Arg23Arg	synonymous_variant	Exon 1 of 5	1	NM_005189.3	ENSP00000308750.4	Q14781-1
CBX2	ENST00000269399.5 link	c.69C>A	p.Arg23Arg	synonymous_variant	Exon 1 of 4	1		ENSP00000269399.5	Q14781-2
CBX2	ENST00000571484.1 link	n.142C>A		non_coding_transcript_exon_variant	Exon 1 of 3	1
ENSG00000295072	ENST00000727760.1 link	n.61+95G>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.000126

AC:

AN:

151272

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:

0.00353

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000295

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000605

AC:

106

AN:

175196

AF XY:

0.000679

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:

0.000274

Gnomad OTH exome

AF:

0.000877

GnomAD4 exome

AF:

0.000286

AC:

403

AN:

1406732

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

272

AN XY:

697694

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31466

American (AMR)

AF:

0.00

AC:

AN:

39802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25006

East Asian (EAS)

AF:

0.00

AC:

AN:

37136

South Asian (SAS)

AF:

0.00314

AC:

254

AN:

80838

European-Finnish (FIN)

AF:

0.0000255

AC:

AN:

39216

Middle Eastern (MID)

AF:

0.000441

AC:

AN:

4538

European-Non Finnish (NFE)

AF:

0.000112

AC:

122

AN:

1090498

Other (OTH)

AF:

0.000412

AC:

AN:

58232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000119

AC:

AN:

151378

Hom.:

Cov.:

AF XY:

0.000176

AC XY:

AN XY:

73966

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41406

American (AMR)

AF:

0.00

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5108

South Asian (SAS)

AF:

0.00333

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10310

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0000295

AC:

AN:

67744

Other (OTH)

AF:

0.00

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.0000491

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CBX2: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.59

PhyloP100

0.13

PromoterAI

0.070

Neutral

(source)

Mutation Taster

=100/0

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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chr17-79778304-C-A

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