8-31063269-C-T

Variant names:

• chr8-31063269-C-T
• rs2015230
• NM_000553.6:c.210-1020C>T

Variant summary

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

The NM_000553.6(WRN):​c.210-1020C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.638 in 152,104 control chromosomes in the GnomAD database, including 31,545 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 0.64 (31545 hom., cov: 34)
• Consequence: WRN NM_000553.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.695
• Publications: 8 publications found

Genes affected

WRN (HGNC:12791): (WRN RecQ like helicase) This gene encodes a member of the RecQ subfamily of DNA helicase proteins. The encoded nuclear protein is important in the maintenance of genome stability and plays a role in DNA repair, replication, transcription and telomere maintenance. This protein contains a N-terminal 3' to 5' exonuclease domain, an ATP-dependent helicase domain and RQC (RecQ helicase conserved region) domain in its central region, and a C-terminal HRDC (helicase RNase D C-terminal) domain and nuclear localization signal. Defects in this gene are the cause of Werner syndrome, an autosomal recessive disorder characterized by accelerated aging and an elevated risk for certain cancers. [provided by RefSeq, Aug 2017]

WRN Gene-Disease associations (from GenCC):

• Werner syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)
• osteosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.798 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000553.6. 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
	WRN	NM_000553.6	MANE Select	c.210-1020C>T		intron	N/A	NP_000544.2	Q14191

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	ENST00000298139.7	TSL:1 MANE Select	c.210-1020C>T		intron	N/A	ENSP00000298139.5	Q14191
	WRN	ENST00000966176.1		c.210-1020C>T		intron	N/A	ENSP00000636235.1
	WRN	ENST00000860283.1		c.210-1020C>T		intron	N/A	ENSP00000530342.1

Frequencies

GnomAD3 genomes AF: 0.638 AC: 97040 AN: 151986 Hom.: 31529 Cov.: 34

Gnomad AFR AF: 0.529

Gnomad AMI AF: 0.693

Gnomad AMR AF: 0.732

Gnomad ASJ AF: 0.700

Gnomad EAS AF: 0.818

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.695

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.661

Gnomad OTH AF: 0.630

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.638 AC: 97098 AN: 152104 Hom.: 31545 Cov.: 34 AF XY: 0.642 AC XY: 47746 AN XY: 74328

African (AFR) AF: 0.529 AC: 21931 AN: 41474

American (AMR) AF: 0.732 AC: 11182 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 2431 AN: 3472

East Asian (EAS) AF: 0.818 AC: 4236 AN: 5176

South Asian (SAS) AF: 0.597 AC: 2880 AN: 4822

European-Finnish (FIN) AF: 0.695 AC: 7352 AN: 10572

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.661 AC: 44924 AN: 67988

Other (OTH) AF: 0.630 AC: 1332 AN: 2114

Alfa AF: 0.641 Hom.: 23868

Bravo AF: 0.640

Asia WGS AF: 0.726 AC: 2521 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.32
DANN	Benign	0.39
PhyloP100		-0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2015230; hg19: chr8-30920785;