13-49490916-A-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001160308.3(SETDB2):c.2006+6A>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00444 in 1,608,664 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0037 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (22 hom.)
• Consequence: SETDB2 NM_001160308.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00009359
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.07

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 13-49490916-A-C is Benign according to our data. Variant chr13-49490916-A-C is described in ClinVar as [Benign]. Clinvar id is 774906.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETDB2	NM_001160308.3	c.2006+6A>C		splice_donor_region_variant, intron_variant		ENST00000611815.2
SETDB2-PHF11	NR_135324.2	n.2662+6A>C		splice_donor_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETDB2	ENST00000611815.2	c.2006+6A>C		splice_donor_region_variant, intron_variant		5	NM_001160308.3	P1
SETDB2	ENST00000317257.12	c.2006+6A>C		splice_donor_region_variant, intron_variant		1		P1
SETDB2	ENST00000354234.8	c.2042+6A>C		splice_donor_region_variant, intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00364 AC: 554 AN: 152220 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00819

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00481

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00430 AC: 1074 AN: 249704 Hom.: 5 AF XY: 0.00425 AC XY: 574 AN XY: 135094

Gnomad AFR exome AF: 0.000560

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00768

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00115

Gnomad FIN exome AF: 0.0108

Gnomad NFE exome AF: 0.00522

Gnomad OTH exome AF: 0.00676

GnomAD4 exome AF: 0.00452 AC: 6587 AN: 1456326 Hom.: 22 Cov.: 27 AF XY: 0.00445 AC XY: 3226 AN XY: 724964

Gnomad4 AFR exome AF: 0.000959

Gnomad4 AMR exome AF: 0.00271

Gnomad4 ASJ exome AF: 0.00687

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00140

Gnomad4 FIN exome AF: 0.0105

Gnomad4 NFE exome AF: 0.00469

Gnomad4 OTH exome AF: 0.00462

GnomAD4 genome AF: 0.00366 AC: 557 AN: 152338 Hom.: 1 Cov.: 33 AF XY: 0.00349 AC XY: 260 AN XY: 74490

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00819

Gnomad4 NFE AF: 0.00482

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00488 Hom.: 0

Bravo AF: 0.00312

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00562

EpiControl AF: 0.00469

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 06, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	18
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000094
dbscSNV1_RF	Benign	0.044
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: rs189713465; hg19: chr13-50065052;