dbSNP rs2057413: SETDB2:p.Val461Met (chr13-49482961-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001160308.3(SETDB2):c.1381G>A(p.Val461Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.726 in 1,589,932 control chromosomes in the GnomAD database, including 422,250 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.78 ( 47632 hom., cov: 32)

Exomes 𝑓: 0.72 ( 374618 hom. )

Consequence

SETDB2
NM_001160308.3 missense, splice_region

Scores

Splicing: ADA: 0.00008348

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.11

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 Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1334412E-6).

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.1381G>A	p.Val461Met	missense_variant, splice_region_variant	Exon 9 of 14	ENST00000611815.2	NP_001153780.1	Q96T68-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SETDB2	ENST00000611815.2 link	c.1381G>A	p.Val461Met	missense_variant, splice_region_variant	Exon 9 of 14	5	NM_001160308.3	ENSP00000482240.2	Q96T68-2A0A087WYZ9
SETDB2	ENST00000354234.8 link	c.1417G>A	p.Val473Met	missense_variant, splice_region_variant	Exon 10 of 15	1		ENSP00000346175.5	Q96T68-1
SETDB2	ENST00000317257.12 link	c.1381G>A	p.Val461Met	missense_variant, splice_region_variant	Exon 8 of 13	1		ENSP00000326477.9	Q96T68-2

Frequencies

GnomAD3 genomes

AF:

0.784

AC:

119239

AN:

152044

Hom.:

47571

Cov.:

show subpopulations

Gnomad AFR

AF:

0.930

Gnomad AMI

AF:

0.746

Gnomad AMR

AF:

0.776

Gnomad ASJ

AF:

0.697

Gnomad EAS

AF:

0.870

Gnomad SAS

AF:

0.728

Gnomad FIN

AF:

0.766

Gnomad MID

AF:

0.728

Gnomad NFE

AF:

0.704

Gnomad OTH

AF:

0.762

GnomAD3 exomes

AF:

0.755

AC:

184644

AN:

244492

Hom.:

70267

AF XY:

0.746

AC XY:

98551

AN XY:

132078

show subpopulations

Gnomad AFR exome

AF:

0.933

Gnomad AMR exome

AF:

0.805

Gnomad ASJ exome

AF:

0.708

Gnomad EAS exome

AF:

0.858

Gnomad SAS exome

AF:

0.721

Gnomad FIN exome

AF:

0.772

Gnomad NFE exome

AF:

0.709

Gnomad OTH exome

AF:

0.736

GnomAD4 exome

AF:

0.719

AC:

1034367

AN:

1437770

Hom.:

374618

Cov.:

AF XY:

0.719

AC XY:

514499

AN XY:

715154

show subpopulations

Gnomad4 AFR exome

AF:

0.934

Gnomad4 AMR exome

AF:

0.796

Gnomad4 ASJ exome

AF:

0.710

Gnomad4 EAS exome

AF:

0.894

Gnomad4 SAS exome

AF:

0.718

Gnomad4 FIN exome

AF:

0.766

Gnomad4 NFE exome

AF:

0.701

Gnomad4 OTH exome

AF:

0.735

GnomAD4 genome

AF:

0.784

AC:

119358

AN:

152162

Hom.:

47632

Cov.:

AF XY:

0.787

AC XY:

58522

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.930

Gnomad4 AMR

AF:

0.776

Gnomad4 ASJ

AF:

0.697

Gnomad4 EAS

AF:

0.870

Gnomad4 SAS

AF:

0.728

Gnomad4 FIN

AF:

0.766

Gnomad4 NFE

AF:

0.704

Gnomad4 OTH

AF:

0.758

Alfa

AF:

0.719

Hom.:

96975

Bravo

AF:

0.791

TwinsUK

AF:

0.700

AC:

2594

ALSPAC

AF:

0.697

AC:

2687

ESP6500AA

AF:

0.933

AC:

4109

ESP6500EA

AF:

0.702

AC:

6035

ExAC

AF:

0.755

AC:

91635

Asia WGS

AF:

0.793

AC:

2756

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

0.89

DANN

Benign

0.056

DEOGEN2

Benign

0.017

T;T;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.00036

LIST_S2

Benign

0.22

T;T;T;T

MetaRNN

Benign

0.0000011

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.84

N;.;.;.

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.26

.;N;.;.

REVEL

Benign

0.064

Sift

Benign

0.31

.;T;.;.

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.0010

B;.;B;.

Vest4

0.026

MPC

0.23

ClinPred

0.013

GERP RS

-0.81

Varity_R

0.022

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000083

dbscSNV1_RF

Benign

0.068

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over