Genetic Variant CBX1:c.319-97G>A (chr17-48075197-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001127228.2(CBX1):c.319-97G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 635,592 control chromosomes in the GnomAD database, including 2,799 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.12 ( 1058 hom., cov: 30)

Exomes 𝑓: 0.11 ( 1741 hom. )

Consequence

CBX1
NM_001127228.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.128

Publications

15 publications found

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 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: G2P

CBX1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBX1	NM_001127228.2 link	c.319-97G>A		intron_variant	Intron 3 of 4	ENST00000225603.9	NP_001120700.1	P83916Q6IBN6
CBX1	NM_006807.5 link	c.319-97G>A		intron_variant	Intron 3 of 4		NP_006798.1	P83916Q6IBN6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBX1	ENST00000225603.9 link	c.319-97G>A		intron_variant	Intron 3 of 4	1	NM_001127228.2	ENSP00000225603.4		P83916

Frequencies

GnomAD3 genomes

AF:

0.117

AC:

17150

AN:

145996

Hom.:

1057

Cov.:

show subpopulations

Gnomad AFR

AF:

0.135

Gnomad AMI

AF:

0.204

Gnomad AMR

AF:

0.0808

Gnomad ASJ

AF:

0.0932

Gnomad EAS

AF:

0.193

Gnomad SAS

AF:

0.117

Gnomad FIN

AF:

0.132

Gnomad MID

AF:

0.156

Gnomad NFE

AF:

0.107

Gnomad OTH

AF:

0.0984

GnomAD4 exome

AF:

0.114

AC:

55831

AN:

489534

Hom.:

1741

AF XY:

0.113

AC XY:

29406

AN XY:

259110

show subpopulations

African (AFR)

AF:

0.154

AC:

1914

AN:

12418

American (AMR)

AF:

0.0726

AC:

1492

AN:

20544

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

1396

AN:

13862

East Asian (EAS)

AF:

0.163

AC:

4659

AN:

28578

South Asian (SAS)

AF:

0.114

AC:

5181

AN:

45420

European-Finnish (FIN)

AF:

0.124

AC:

4568

AN:

36702

Middle Eastern (MID)

AF:

0.150

AC:

506

AN:

3366

European-Non Finnish (NFE)

AF:

0.110

AC:

33252

AN:

303230

Other (OTH)

AF:

0.113

AC:

2863

AN:

25414

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

1823

3646

5469

7292

9115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

564

1128

1692

2256

2820

<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:

0.118

AC:

17162

AN:

146058

Hom.:

1058

Cov.:

AF XY:

0.117

AC XY:

8328

AN XY:

70910

show subpopulations

African (AFR)

AF:

0.135

AC:

5442

AN:

40266

American (AMR)

AF:

0.0808

AC:

1173

AN:

14512

Ashkenazi Jewish (ASJ)

AF:

0.0932

AC:

317

AN:

3400

East Asian (EAS)

AF:

0.193

AC:

960

AN:

4980

South Asian (SAS)

AF:

0.117

AC:

539

AN:

4592

European-Finnish (FIN)

AF:

0.132

AC:

1227

AN:

9272

Middle Eastern (MID)

AF:

0.153

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.107

AC:

7079

AN:

65876

Other (OTH)

AF:

0.101

AC:

202

AN:

1996

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

730

1460

2191

2921

3651

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

194

388

582

776

970

<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:

0.00626

Hom.:

1742

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

2.1

(source)

DANN

Benign

0.89

PhyloP100

0.13

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over