rs4451553

Variant names:

• chr1-150964853-C-T
• rs4451553
• ENST00000561294.5:c.976-378G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000561294.5(CERS2):​c.976-378G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 288,790 control chromosomes in the GnomAD database, including 19,359 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.34 (9423 hom., cov: 32)
  • Exomes 𝑓: 0.37 (9936 hom.)
• Consequence: CERS2 ENST00000561294.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.326
• Publications: 18 publications found

Genes affected

CERS2 (HGNC:14076): (ceramide synthase 2) This gene encodes a protein that has sequence similarity to yeast longevity assurance gene 1. Mutation or overexpression of the related gene in yeast has been shown to alter yeast lifespan. The human protein may play a role in the regulation of cell growth. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jul 2008]

SETDB1 (HGNC:10761): (SET domain bifurcated histone lysine methyltransferase 1) This gene encodes a histone methyltransferase which regulates histone methylation, gene silencing, and transcriptional repression. This gene has been identified as a target for treatment in Huntington Disease, given that gene silencing and transcription dysfunction likely play a role in the disease pathogenesis. Alternatively spliced transcript variants of this gene have been described.[provided by RefSeq, Jun 2011]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETDB1	NM_001366418.1	c.*489C>T		downstream_gene_variant		ENST00000692827.1	NP_001353347.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETDB1	ENST00000692827.1	c.*489C>T		downstream_gene_variant			NM_001366418.1	ENSP00000509425.1

Frequencies

GnomAD3 genomes AF: 0.345 AC: 52411 AN: 151872 Hom.: 9412 Cov.: 32

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.465

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.413

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.340

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.355

GnomAD4 exome AF: 0.372 AC: 50882 AN: 136798 Hom.: 9936 AF XY: 0.379 AC XY: 26080 AN XY: 68824

African (AFR) AF: 0.274 AC: 1312 AN: 4784

American (AMR) AF: 0.505 AC: 2795 AN: 5534

Ashkenazi Jewish (ASJ) AF: 0.399 AC: 2137 AN: 5352

East Asian (EAS) AF: 0.457 AC: 5370 AN: 11760

South Asian (SAS) AF: 0.488 AC: 5791 AN: 11860

European-Finnish (FIN) AF: 0.349 AC: 1455 AN: 4170

Middle Eastern (MID) AF: 0.373 AC: 238 AN: 638

European-Non Finnish (NFE) AF: 0.341 AC: 28604 AN: 83808

Other (OTH) AF: 0.358 AC: 3180 AN: 8892

GnomAD4 genome AF: 0.345 AC: 52433 AN: 151992 Hom.: 9423 Cov.: 32 AF XY: 0.351 AC XY: 26062 AN XY: 74294

African (AFR) AF: 0.275 AC: 11376 AN: 41432

American (AMR) AF: 0.466 AC: 7104 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 1420 AN: 3468

East Asian (EAS) AF: 0.413 AC: 2134 AN: 5170

South Asian (SAS) AF: 0.505 AC: 2436 AN: 4820

European-Finnish (FIN) AF: 0.340 AC: 3586 AN: 10560

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.342 AC: 23266 AN: 67972

Other (OTH) AF: 0.358 AC: 756 AN: 2110

Alfa AF: 0.353 Hom.: 4891

Bravo AF: 0.350

Asia WGS AF: 0.426 AC: 1477 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.7
DANN	Benign	0.50
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs4451553; hg19: chr1-150937329;