13-49482866-T-G

Variant names:

• chr13-49482866-T-G
• rs148980682
• NM_001160308.3:c.1286T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001160308.3(SETDB2):​c.1286T>G​(p.Val429Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V429A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SETDB2 NM_001160308.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07203865).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001160308.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETDB2	NM_001160308.3	MANE Select	c.1286T>G	p.Val429Gly	missense	Exon 9 of 14	NP_001153780.1	Q96T68-2
	SETDB2-PHF11	NM_001320727.2		c.1286T>G	p.Val429Gly	missense	Exon 9 of 20	NP_001307656.1
	SETDB2	NM_031915.3		c.1322T>G	p.Val441Gly	missense	Exon 10 of 15	NP_114121.2	Q96T68-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETDB2	ENST00000611815.2	TSL:5 MANE Select	c.1286T>G	p.Val429Gly	missense	Exon 9 of 14	ENSP00000482240.2	Q96T68-2
	SETDB2	ENST00000354234.8	TSL:1	c.1322T>G	p.Val441Gly	missense	Exon 10 of 15	ENSP00000346175.5	Q96T68-1
	SETDB2	ENST00000317257.12	TSL:1	c.1286T>G	p.Val429Gly	missense	Exon 8 of 13	ENSP00000326477.9	Q96T68-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461264 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726956

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111694

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.5
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.14
Sift	Benign	0.10	T
Sift4G	Benign	0.077	T
Polyphen		0.012	B
Vest4		0.18
MutPred		0.44		Gain of catalytic residue at V443 (P = 2e-04)
MVP		0.20
MPC		0.31
ClinPred		0.10	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.067
gMVP		0.84
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs148980682; hg19: chr13-50057002;