rs2057413

Variant names:

• chr13-49482961-G-A
• rs2057413
• NM_001160308.3:c.1381G>A

Variant summary

Our verdict is Benign. The variant received -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. 17/23 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
• Publications: 47 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001160308.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETDB2	NM_001160308.3	MANE Select	c.1381G>A	p.Val461Met	missense splice_region	Exon 9 of 14	NP_001153780.1	Q96T68-2
	SETDB2-PHF11	NM_001320727.2		c.1381G>A	p.Val461Met	missense splice_region	Exon 9 of 20	NP_001307656.1
	SETDB2	NM_031915.3		c.1417G>A	p.Val473Met	missense splice_region	Exon 10 of 15	NP_114121.2	Q96T68-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETDB2	ENST00000611815.2	TSL:5 MANE Select	c.1381G>A	p.Val461Met	missense splice_region	Exon 9 of 14	ENSP00000482240.2	Q96T68-2
	SETDB2	ENST00000354234.8	TSL:1	c.1417G>A	p.Val473Met	missense splice_region	Exon 10 of 15	ENSP00000346175.5	Q96T68-1
	SETDB2	ENST00000317257.12	TSL:1	c.1381G>A	p.Val461Met	missense splice_region	Exon 8 of 13	ENSP00000326477.9	Q96T68-2

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

GnomAD2 exomes AF: 0.755 AC: 184644 AN: 244492 AF XY: 0.746

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 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

African (AFR) AF: 0.934 AC: 30481 AN: 32650

American (AMR) AF: 0.796 AC: 34409 AN: 43240

Ashkenazi Jewish (ASJ) AF: 0.710 AC: 18215 AN: 25668

East Asian (EAS) AF: 0.894 AC: 35218 AN: 39412

South Asian (SAS) AF: 0.718 AC: 59901 AN: 83462

European-Finnish (FIN) AF: 0.766 AC: 40761 AN: 53190

Middle Eastern (MID) AF: 0.729 AC: 4157 AN: 5704

European-Non Finnish (NFE) AF: 0.701 AC: 767509 AN: 1094974

Other (OTH) AF: 0.735 AC: 43716 AN: 59470

GnomAD4 genome AF: 0.784 AC: 119358 AN: 152162 Hom.: 47632 Cov.: 32 AF XY: 0.787 AC XY: 58522 AN XY: 74378

African (AFR) AF: 0.930 AC: 38644 AN: 41562

American (AMR) AF: 0.776 AC: 11867 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.697 AC: 2416 AN: 3466

East Asian (EAS) AF: 0.870 AC: 4502 AN: 5176

South Asian (SAS) AF: 0.728 AC: 3501 AN: 4812

European-Finnish (FIN) AF: 0.766 AC: 8095 AN: 10564

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.704 AC: 47837 AN: 67974

Other (OTH) AF: 0.758 AC: 1601 AN: 2112

Alfa AF: 0.726 Hom.: 134033

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 v4.9

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00036	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.84	N
PhyloP100		-1.1
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.064
Sift	Benign	0.31	T
Sift4G	Benign	0.17	T
Polyphen		0.0010	B
Vest4		0.026
MPC		0.23
ClinPred		0.013	T
GERP RS		-0.81
Varity_R		0.022
gMVP		0.11
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2057413; hg19: chr13-50057097; COSMIC: COSV107256254;