Genetic Variant SETDB2:c.1577-99C>T (chr13-49488191-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_001160308.3(SETDB2):c.1577-99C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.724 in 1,458,604 control chromosomes in the GnomAD database, including 385,978 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 0.78 ( 47627 hom., cov: 31)

Exomes 𝑓: 0.72 ( 338351 hom. )

Consequence

SETDB2
NM_001160308.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.151

Publications

11 publications found

Variant links:

Genes affected

SETDB2 (HGNC:20263): (SET domain bifurcated histone lysine methyltransferase 2) This gene encodes a member of a family of proteins that contain a methyl-CpG-binding domain (MBD) and a SET domain and function as histone methyltransferases. This protein is recruited to heterochromatin and plays a role in the regulation of chromosome segregation. This region is commonly deleted in chronic lymphocytic leukemia. Naturally-occuring readthrough transcription occurs from this gene to the downstream PHF11 (PHD finger protein 11) gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

SETDB2 links:

SETDB2-PHF11 (HGNC:):

SETDB2-PHF11 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=-0.87).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.922 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETDB2	NM_001160308.3 link	c.1577-99C>T		intron_variant	Intron 11 of 13	ENST00000611815.2	NP_001153780.1	Q96T68-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SETDB2	ENST00000611815.2 link	c.1577-99C>T	intron_variant	Intron 11 of 13	5	NM_001160308.3	ENSP00000482240.2	Q96T68-2A0A087WYZ9
SETDB2	ENST00000354234.8 link	c.1613-99C>T	intron_variant	Intron 12 of 14	1		ENSP00000346175.5	Q96T68-1
SETDB2	ENST00000317257.12 link	c.1577-99C>T	intron_variant	Intron 10 of 12	1		ENSP00000326477.9	Q96T68-2

Frequencies

GnomAD3 genomes

AF:

0.784

AC:

119229

AN:

151986

Hom.:

47566

Cov.:

show subpopulations

Gnomad AFR

AF:

0.930

Gnomad AMI

AF:

0.747

Gnomad AMR

AF:

0.776

Gnomad ASJ

AF:

0.697

Gnomad EAS

AF:

0.869

Gnomad SAS

AF:

0.729

Gnomad FIN

AF:

0.767

Gnomad MID

AF:

0.728

Gnomad NFE

AF:

0.704

Gnomad OTH

AF:

0.763

GnomAD4 exome

AF:

0.717

AC:

937248

AN:

1306500

Hom.:

338351

Cov.:

AF XY:

0.718

AC XY:

458422

AN XY:

638656

show subpopulations

African (AFR)

AF:

0.935

AC:

27481

AN:

29402

American (AMR)

AF:

0.785

AC:

17695

AN:

22536

Ashkenazi Jewish (ASJ)

AF:

0.708

AC:

13588

AN:

19200

East Asian (EAS)

AF:

0.895

AC:

33784

AN:

37758

South Asian (SAS)

AF:

0.718

AC:

44213

AN:

61620

European-Finnish (FIN)

AF:

0.765

AC:

27261

AN:

35646

Middle Eastern (MID)

AF:

0.731

AC:

2677

AN:

3662

European-Non Finnish (NFE)

AF:

0.701

AC:

730945

AN:

1042678

Other (OTH)

AF:

0.733

AC:

39604

AN:

53998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

12306

24612

36919

49225

61531

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19316

38632

57948

77264

96580

<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:

0.785

AC:

119348

AN:

152104

Hom.:

47627

Cov.:

AF XY:

0.787

AC XY:

58506

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.930

AC:

38625

AN:

41530

American (AMR)

AF:

0.776

AC:

11863

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.697

AC:

2416

AN:

3468

East Asian (EAS)

AF:

0.869

AC:

4492

AN:

5168

South Asian (SAS)

AF:

0.729

AC:

3510

AN:

4816

European-Finnish (FIN)

AF:

0.767

AC:

8094

AN:

10558

Middle Eastern (MID)

AF:

0.731

AC:

215

AN:

294

European-Non Finnish (NFE)

AF:

0.704

AC:

47852

AN:

67968

Other (OTH)

AF:

0.759

AC:

1603

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1284

2568

3853

5137

6421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

860

1720

2580

3440

4300

<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:

0.745

Hom.:

4551

Bravo

AF:

0.791

Asia WGS

AF:

0.794

AC:

2759

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

8.7

(source)

DANN

Benign

0.66

PhyloP100

-0.15

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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