13-49485649-C-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.1502C>G(p.Ser501Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S501T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SETDB2 NM_001160308.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23

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=0.16767353).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETDB2	NM_001160308.3	c.1502C>G	p.Ser501Cys	missense_variant	11/14	ENST00000611815.2
SETDB2-PHF11	NR_135324.2	n.2573+2086C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETDB2	ENST00000611815.2	c.1502C>G	p.Ser501Cys	missense_variant	11/14	5	NM_001160308.3	P1
SETDB2	ENST00000354234.8	c.1538C>G	p.Ser513Cys	missense_variant	12/15	1
SETDB2	ENST00000317257.12	c.1502C>G	p.Ser501Cys	missense_variant	10/13	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Oct 27, 2022

The c.1538C>G (p.S513C) alteration is located in exon 12 (coding exon 11) of the SETDB2 gene. This alteration results from a C to G substitution at nucleotide position 1538, causing the serine (S) at amino acid position 513 to be replaced by a cysteine (C). 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	0.089
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	22
Dann	Benign	0.96
DEOGEN2	Benign	0.080	T;T;.;.
Eigen	Benign	-0.0073
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.3	M;.;.;.
MutationTaster	Benign	0.79	D;D;D
PrimateAI	Benign	0.33	T
REVEL	Uncertain	0.33
Sift4G	Benign	0.26	T;T;T;T
Polyphen		0.091	B;.;B;.
Vest4		0.17
MutPred		0.39		Gain of catalytic residue at E512 (P = 5e-04);.;.;Gain of catalytic residue at E512 (P = 5e-04);
MVP		0.58
MPC		0.29
ClinPred		0.32	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.068
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-50059785;