13-49483555-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001160308.3(SETDB2):c.1474A>G(p.Lys492Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000156 in 1,282,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SETDB2 NM_001160308.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0510

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08887634).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETDB2	NM_001160308.3	c.1474A>G	p.Lys492Glu	missense_variant	10/14	ENST00000611815.2
SETDB2-PHF11	NR_135324.2	n.2565A>G		non_coding_transcript_exon_variant	11/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETDB2	ENST00000611815.2	c.1474A>G	p.Lys492Glu	missense_variant	10/14	5	NM_001160308.3	P1
SETDB2	ENST00000354234.8	c.1510A>G	p.Lys504Glu	missense_variant	11/15	1
SETDB2	ENST00000317257.12	c.1474A>G	p.Lys492Glu	missense_variant	9/13	1		P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000222 AC: 4 AN: 179834 Hom.: 0 AF XY: 0.0000101 AC XY: 1 AN XY: 99332

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: 0.000147

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000256

GnomAD4 exome AF: 0.0000156 AC: 20 AN: 1282968 Hom.: 0 Cov.: 20 AF XY: 0.0000203 AC XY: 13 AN XY: 641034

Gnomad4 AFR exome AF: 0.0000373

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000441

Gnomad4 FIN exome AF: 0.000215

Gnomad4 NFE exome AF: 0.00000201

Gnomad4 OTH exome AF: 0.0000375

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2023

The c.1510A>G (p.K504E) alteration is located in exon 11 (coding exon 10) of the SETDB2 gene. This alteration results from a A to G substitution at nucleotide position 1510, causing the lysine (K) at amino acid position 504 to be replaced by a glutamic acid (E). 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	0.075
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	5.4
Dann	Uncertain	0.98
DEOGEN2	Benign	0.028	T;T;.;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.56	T;T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.089	T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.8	L;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
REVEL	Benign	0.15
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.085	B;.;B;.
Vest4		0.13
MutPred		0.50		Gain of catalytic residue at F499 (P = 0.0017);.;.;Gain of catalytic residue at F499 (P = 0.0017);
MVP		0.25
MPC		0.41
ClinPred		0.13	T
GERP RS		0.30
Varity_R		0.063
gMVP		0.24

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: rs751675287; hg19: chr13-50057691;