Genetic Variant CBX2:p.Ile49Ile (chr17-79779392-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_005189.3(CBX2):c.147C>T(p.Ile49Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0239 in 1,613,810 control chromosomes in the GnomAD database, including 539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 53 hom., cov: 33)

Exomes 𝑓: 0.024 ( 486 hom. )

Consequence

CBX2
NM_005189.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0500

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

46,XY complete gonadal dysgenesis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
46,XY sex reversal 5
Inheritance: AR, SD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

CBX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 17-79779392-C-T is Benign according to our data. Variant chr17-79779392-C-T is described in ClinVar as Benign. ClinVar VariationId is 1614331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.05 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0191 (2909/152290) while in subpopulation NFE AF = 0.0277 (1883/68012). AF 95% confidence interval is 0.0266. There are 53 homozygotes in GnomAd4. There are 1406 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 53 SD,AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005189.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBX2	NM_005189.3	MANE Select	c.147C>T	p.Ile49Ile	synonymous	Exon 3 of 5	NP_005180.1	Q14781-1
	CBX2	NM_032647.4		c.147C>T	p.Ile49Ile	synonymous	Exon 3 of 4	NP_116036.1	Q14781-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CBX2	ENST00000310942.9	TSL:1 MANE Select	c.147C>T	p.Ile49Ile	synonymous	Exon 3 of 5	ENSP00000308750.4	Q14781-1
CBX2	ENST00000269399.5	TSL:1	c.147C>T	p.Ile49Ile	synonymous	Exon 3 of 4	ENSP00000269399.5	Q14781-2
CBX2	ENST00000571484.1	TSL:1	n.220C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.0191

AC:

2910

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00388

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0253

Gnomad ASJ

AF:

0.0259

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.0200

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0277

Gnomad OTH

AF:

0.0421

GnomAD2 exomes

AF:

0.0216

AC:

5399

AN:

250212

AF XY:

0.0226

show subpopulations

Gnomad AFR exome

AF:

0.00297

Gnomad AMR exome

AF:

0.0193

Gnomad ASJ exome

AF:

0.0258

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0185

Gnomad NFE exome

AF:

0.0299

Gnomad OTH exome

AF:

0.0298

GnomAD4 exome

AF:

0.0244

AC:

35685

AN:

1461520

Hom.:

486

Cov.:

AF XY:

0.0244

AC XY:

17748

AN XY:

727058

show subpopulations

African (AFR)

AF:

0.00406

AC:

136

AN:

33480

American (AMR)

AF:

0.0208

AC:

932

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

617

AN:

26128

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0155

AC:

1335

AN:

86232

European-Finnish (FIN)

AF:

0.0191

AC:

1019

AN:

53232

Middle Eastern (MID)

AF:

0.0515

AC:

296

AN:

5746

European-Non Finnish (NFE)

AF:

0.0268

AC:

29785

AN:

1111908

Other (OTH)

AF:

0.0258

AC:

1560

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

1856

3713

5569

7426

9282

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1068

2136

3204

4272

5340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0191

AC:

2909

AN:

152290

Hom.:

Cov.:

AF XY:

0.0189

AC XY:

1406

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00387

AC:

161

AN:

41572

American (AMR)

AF:

0.0252

AC:

386

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0259

AC:

AN:

3472

East Asian (EAS)

AF:

0.000387

AC:

AN:

5174

South Asian (SAS)

AF:

0.0147

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0200

AC:

212

AN:

10610

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0277

AC:

1883

AN:

68012

Other (OTH)

AF:

0.0417

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

145

290

434

579

724

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0257

Hom.:

110

Bravo

AF:

0.0188

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.0363

EpiControl

AF:

0.0341

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

0.050

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=97/3

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over