Variant chr13-49467915-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001160308.3(SETDB2):c.260C>T(p.Pro87Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SETDB2
NM_001160308.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.23

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 made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31553245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETDB2	NM_001160308.3 linkuse as main transcript	c.260C>T	p.Pro87Leu	missense_variant	5/14	ENST00000611815.2	NP_001153780.1	Q96T68-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SETDB2	ENST00000611815.2 linkuse as main transcript	c.260C>T	p.Pro87Leu	missense_variant	5/14	5	NM_001160308.3	ENSP00000482240.2	Q96T68-2A0A087WYZ9
SETDB2	ENST00000354234.8 linkuse as main transcript	c.296C>T	p.Pro99Leu	missense_variant	6/15	1		ENSP00000346175.5	Q96T68-1
SETDB2	ENST00000317257.12 linkuse as main transcript	c.260C>T	p.Pro87Leu	missense_variant	4/13	1		ENSP00000326477.9	Q96T68-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000803

AC:

AN:

248936

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134682

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1458676

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725680

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.000111

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2023

The c.296C>T (p.P99L) alteration is located in exon 6 (coding exon 5) of the SETDB2 gene. This alteration results from a C to T substitution at nucleotide position 296, causing the proline (P) at amino acid position 99 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.16

T;T;.;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.77

T;T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.32

T;T;T;T

MetaSVM

Uncertain

0.60

MutationAssessor

Uncertain

2.3

M;.;.;.

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.3

.;D;.;.

REVEL

Benign

0.25

Sift

Uncertain

0.0020

.;D;.;.

Sift4G

Benign

0.70

T;T;T;T

Polyphen

0.78

P;.;P;.

Vest4

0.48

MutPred

0.29

Gain of catalytic residue at E104 (P = 0.0416);.;.;Gain of catalytic residue at E104 (P = 0.0416);

MVP

0.63

MPC

0.80

ClinPred

0.83

GERP RS

5.0

Varity_R

0.094

gMVP

0.35

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over