rs2057413

chr13-49482961-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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

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-PHF11 (HGNC:):

ACMG classification

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/exons	MANE	UniProt
SETDB2	NM_001160308.3	c.1381G>A	p.Val461Met	missense_variant, splice_region_variant	9/14	ENST00000611815.2
SETDB2-PHF11	NR_135324.2	n.2472G>A		splice_region_variant, non_coding_transcript_exon_variant	10/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETDB2	ENST00000611815.2	c.1381G>A	p.Val461Met	missense_variant, splice_region_variant	9/14	5	NM_001160308.3	P1
SETDB2	ENST00000354234.8	c.1417G>A	p.Val473Met	missense_variant, splice_region_variant	10/15	1
SETDB2	ENST00000317257.12	c.1381G>A	p.Val461Met	missense_variant, splice_region_variant	8/13	1		P1

Frequencies

GnomAD3 genomes AF: 0.784 AC: 119239 AN: 152044 Hom.: 47571 Cov.: 32

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

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.: 25 AF XY: 0.719 AC XY: 514499 AN XY: 715154

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.: 32 AF XY: 0.787 AC XY: 58522 AN XY: 74378

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	T
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	N
LIST_S2	Benign	0.22	T;T;T;T
MetaRNN	Benign	0.0000011	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.84	N;.;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.23	T
REVEL	Benign	0.064
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.0010	B;.;B;.
Vest4		0.026
MPC		0.23
ClinPred		0.013	T
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

Other links and lift over

dbSNP: rs2057413; hg19: chr13-50057097;