Genetic Variant NM_005189.3:c.72+25delC (chr17-79778326-GC-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_005189.3(CBX2):c.72+25delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000283 in 1,411,214 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CBX2
NM_005189.3 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.584

Publications

0 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:

ENSG00000295072 (HGNC:):

ENSG00000295072 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP6

Variant 17-79778326-GC-G is Benign according to our data. Variant chr17-79778326-GC-G is described in ClinVar as Benign. ClinVar VariationId is 1600780.Status of the report is criteria_provided_single_submitter, 1 stars.

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.72+25delC		intron	N/A	NP_005180.1	Q14781-1
	CBX2	NM_032647.4		c.72+25delC		intron	N/A	NP_116036.1	Q14781-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CBX2	ENST00000310942.9	TSL:1 MANE Select	c.72+20delC	intron	N/A	ENSP00000308750.4	Q14781-1
CBX2	ENST00000269399.5	TSL:1	c.72+20delC	intron	N/A	ENSP00000269399.5	Q14781-2
CBX2	ENST00000571484.1	TSL:1	n.145+20delC	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

150898

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000109

AC:

AN:

182764

AF XY:

0.000128

show subpopulations

Gnomad AFR exome

AF:

0.000211

Gnomad AMR exome

AF:

0.0000686

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000692

Gnomad FIN exome

AF:

0.000296

Gnomad NFE exome

AF:

0.0000989

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000283

AC:

AN:

1411214

Hom.:

Cov.:

AF XY:

0.0000243

AC XY:

AN XY:

700338

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000632

AC:

AN:

31636

American (AMR)

AF:

0.0000736

AC:

AN:

40782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25080

East Asian (EAS)

AF:

0.000319

AC:

AN:

37580

South Asian (SAS)

AF:

0.0000614

AC:

AN:

81496

European-Finnish (FIN)

AF:

0.0000250

AC:

AN:

40008

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4720

European-Non Finnish (NFE)

AF:

0.0000137

AC:

AN:

1091526

Other (OTH)

AF:

0.0000343

AC:

AN:

58386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000024123), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

150898

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73684

African (AFR)

AF:

0.00

AC:

AN:

41150

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:

5076

South Asian (SAS)

AF:

0.00

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67620

Other (OTH)

AF:

0.00

AC:

AN:

2082

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.58

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over