Genetic Variant CBX5:c.-43+3394G>A (chr12-54276614-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_012117.3(CBX5):c.-43+3394G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.519 in 152,038 control chromosomes in the GnomAD database, including 22,518 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 0.52 ( 22517 hom., cov: 32)

Exomes 𝑓: 0.75 ( 1 hom. )

Consequence

CBX5
NM_012117.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.609

Publications

14 publications found

Variant links:

Genes affected

CBX5 (HGNC:1555): (chromobox 5) 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 encoded product is involved in the formation of functional kinetochore through interaction with essential kinetochore proteins. The gene has a pseudogene located on chromosome 3. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

CBX5 links:

SCAT2 (HGNC:53976): (S-phase cancer associated transcript 2)

SCAT2 links:

ENSG00000258344 (HGNC:):

ENSG00000258344 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=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.751 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBX5	NM_012117.3 link	c.-43+3394G>A		intron_variant	Intron 1 of 4	ENST00000209875.9	NP_036249.1	P45973V9HWG0
SCAT2	NR_157844.1 link	n.324-2038C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CBX5	ENST00000209875.9 link	c.-43+3394G>A	intron_variant	Intron 1 of 4	1	NM_012117.3	ENSP00000209875.4	P45973
SCAT2	ENST00000547177.1 link	n.324-2038C>T	intron_variant	Intron 1 of 1	3
CBX5	ENST00000618078.1 link	n.127-2273G>A	intron_variant	Intron 1 of 1	2
ENSG00000258344	ENST00000553061.1 link	n.-17C>T	upstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.519

AC:

78774

AN:

151916

Hom.:

22469

Cov.:

show subpopulations

Gnomad AFR

AF:

0.758

Gnomad AMI

AF:

0.244

Gnomad AMR

AF:

0.500

Gnomad ASJ

AF:

0.283

Gnomad EAS

AF:

0.517

Gnomad SAS

AF:

0.562

Gnomad FIN

AF:

0.487

Gnomad MID

AF:

0.290

Gnomad NFE

AF:

0.398

Gnomad OTH

AF:

0.455

GnomAD4 exome

AF:

0.750

AC:

AN:

Hom.:

Cov.:

AF XY:

0.750

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.750

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.519

AC:

78881

AN:

152034

Hom.:

22517

Cov.:

AF XY:

0.523

AC XY:

38835

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.758

AC:

31438

AN:

41466

American (AMR)

AF:

0.500

AC:

7642

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.283

AC:

980

AN:

3468

East Asian (EAS)

AF:

0.518

AC:

2675

AN:

5166

South Asian (SAS)

AF:

0.560

AC:

2698

AN:

4820

European-Finnish (FIN)

AF:

0.487

AC:

5149

AN:

10572

Middle Eastern (MID)

AF:

0.284

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.398

AC:

27033

AN:

67958

Other (OTH)

AF:

0.455

AC:

961

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1733

3466

5199

6932

8665

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

676

1352

2028

2704

3380

<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:

0.422

Hom.:

24071

Bravo

AF:

0.528

Asia WGS

AF:

0.579

AC:

2013

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.1

(source)

DANN

Benign

0.63

PhyloP100

-0.61

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over