13-49482790-G-A

Position:

• chr13-49482790-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001160308.3(SETDB2):​c.1210G>A​(p.Gly404Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,612,520 control chromosomes in the GnomAD database, including 164 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (40 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (124 hom.)
• Consequence: SETDB2 NM_001160308.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.162

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022360682).
• BP6: Variant 13-49482790-G-A is Benign according to our data. Variant chr13-49482790-G-A is described in ClinVar as [Benign]. Clinvar id is 791038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETDB2	NM_001160308.3	c.1210G>A	p.Gly404Arg	missense_variant	9/14	ENST00000611815.2	NP_001153780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETDB2	ENST00000611815.2	c.1210G>A	p.Gly404Arg	missense_variant	9/14	5	NM_001160308.3	ENSP00000482240.2
SETDB2	ENST00000354234.8	c.1246G>A	p.Gly416Arg	missense_variant	10/15	1		ENSP00000346175.5
SETDB2	ENST00000317257.12	c.1210G>A	p.Gly404Arg	missense_variant	8/13	1		ENSP00000326477.9

Frequencies

GnomAD3 genomes AF: 0.00697 AC: 1060 AN: 152102 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.00396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0564

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0102 AC: 2556 AN: 250698 Hom.: 96 AF XY: 0.00799 AC XY: 1084 AN XY: 135610

Gnomad AFR exome AF: 0.00504

Gnomad AMR exome AF: 0.0693

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00239

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00492

GnomAD4 exome AF: 0.00240 AC: 3502 AN: 1460300 Hom.: 124 Cov.: 30 AF XY: 0.00210 AC XY: 1526 AN XY: 726492

Gnomad4 AFR exome AF: 0.00467

Gnomad4 AMR exome AF: 0.0687

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00185

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.00265

GnomAD4 genome AF: 0.00708 AC: 1077 AN: 152220 Hom.: 40 Cov.: 32 AF XY: 0.00797 AC XY: 593 AN XY: 74422

Gnomad4 AFR AF: 0.00404

Gnomad4 AMR AF: 0.0572

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.000817 Hom.: 3

Bravo AF: 0.0105

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00741 AC: 899

Asia WGS AF: 0.00376 AC: 13 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 20, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.1
DANN	Benign	0.33
DEOGEN2	Benign	0.036	T;T;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.70	T;T;T;T
MetaRNN	Benign	0.0022	T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.55	N;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	.;N;.;.
REVEL	Benign	0.14
Sift	Benign	0.35	.;T;.;.
Sift4G	Benign	0.69	T;T;T;T
Polyphen		0.0010	B;.;B;.
Vest4		0.13
MutPred		0.48		Gain of catalytic residue at G416 (P = 0.0423);.;.;Gain of catalytic residue at G416 (P = 0.0423);
MPC		0.28
ClinPred		0.0011	T
GERP RS		0.52
Varity_R		0.020
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs111983452; hg19: chr13-50056926;