chr13-49480967-T-C

Position:

• chr13-49480967-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001160308.3(SETDB2):​c.1007T>C​(p.Leu336Ser) 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. 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: 33)
• Consequence: SETDB2 NM_001160308.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34606937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETDB2	NM_001160308.3	c.1007T>C	p.Leu336Ser	missense_variant	8/14	ENST00000611815.2	NP_001153780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETDB2	ENST00000611815.2	c.1007T>C	p.Leu336Ser	missense_variant	8/14	5	NM_001160308.3	ENSP00000482240.2
SETDB2	ENST00000354234.8	c.1043T>C	p.Leu348Ser	missense_variant	9/15	1		ENSP00000346175.5
SETDB2	ENST00000317257.12	c.1007T>C	p.Leu336Ser	missense_variant	7/13	1		ENSP00000326477.9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Jan 27, 2022

The c.1043T>C (p.L348S) alteration is located in exon 9 (coding exon 8) of the SETDB2 gene. This alteration results from a T to C substitution at nucleotide position 1043, causing the leucine (L) at amino acid position 348 to be replaced by a serine (S). 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	0.15
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T;.;.
Eigen	Benign	0.064
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.77	T;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.020	N;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.1	.;N;.;.
REVEL	Benign	0.25
Sift	Benign	0.61	.;T;.;.
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.96	D;.;P;.
Vest4		0.28
MutPred		0.52		Gain of catalytic residue at K350 (P = 5e-04);.;.;Gain of catalytic residue at K350 (P = 5e-04);
MVP		0.75
MPC		0.99
ClinPred		0.75	D
GERP RS		5.6
Varity_R		0.082
gMVP		0.67

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: chr13-50055103;