13-49476864-G-T

Variant summary

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

The NM_001160308.3(SETDB2):c.694G>T(p.Val232Leu) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SETDB2 NM_001160308.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.473

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=0.123338014).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETDB2	NM_001160308.3	c.694G>T	p.Val232Leu	missense_variant	6/14	ENST00000611815.2
SETDB2-PHF11	NR_135324.2	n.1619G>T		non_coding_transcript_exon_variant	6/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETDB2	ENST00000611815.2	c.694G>T	p.Val232Leu	missense_variant	6/14	5	NM_001160308.3	P1
SETDB2	ENST00000354234.8	c.730G>T	p.Val244Leu	missense_variant	7/15	1
SETDB2	ENST00000317257.12	c.694G>T	p.Val232Leu	missense_variant	5/13	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

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

Feb 15, 2023

The c.730G>T (p.V244L) alteration is located in exon 7 (coding exon 6) of the SETDB2 gene. This alteration results from a G to T substitution at nucleotide position 730, causing the valine (V) at amino acid position 244 to be replaced by a leucine (L). 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	0.11
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	15
Dann	Benign	0.67
DEOGEN2	Benign	0.0060	T;T;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.060	N;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.40	T
REVEL	Benign	0.17
Sift4G	Benign	0.85	T;T;T;T
Polyphen		0.0010	B;.;B;.
Vest4		0.032
MutPred		0.34		Gain of catalytic residue at N248 (P = 4e-04);.;.;Gain of catalytic residue at N248 (P = 4e-04);
MVP		0.50
MPC		0.23
ClinPred		0.067	T
GERP RS		1.9
Varity_R		0.046
gMVP		0.49

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

LitVar

Other links and lift over

dbSNP: rs1958376442; hg19: chr13-50051000;