rs2230010

Variant names:

• chr8-31081182-G-A
• rs2230010
• NM_000553.6:c.1155G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-31081182-G-A
• chr8-31081182-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000553.6(WRN):​c.1155G>A​(p.Glu385Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00354 in 1,614,008 control chromosomes in the GnomAD database, including 166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (67 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (99 hom.)
• Consequence: WRN NM_000553.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.988
• Publications: 5 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• osteosarcoma

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-31081182-G-A is Benign according to our data. Variant chr8-31081182-G-A is described in ClinVar as Benign. ClinVar VariationId is 362799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.988 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0621 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	NM_000553.6	MANE Select	c.1155G>A	p.Glu385Glu	synonymous	Exon 9 of 35	NP_000544.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WRN	ENST00000298139.7	TSL:1 MANE Select	c.1155G>A	p.Glu385Glu	synonymous	Exon 9 of 35	ENSP00000298139.5
	WRN	ENST00000966176.1		c.1155G>A	p.Glu385Glu	synonymous	Exon 9 of 35	ENSP00000636235.1
	WRN	ENST00000860283.1		c.1155G>A	p.Glu385Glu	synonymous	Exon 9 of 35	ENSP00000530342.1

Frequencies

GnomAD3 genomes AF: 0.0183 AC: 2783 AN: 152152 Hom.: 67 Cov.: 32

Gnomad AFR AF: 0.0642

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00491 AC: 1230 AN: 250478 AF XY: 0.00366

Gnomad AFR exome AF: 0.0664

Gnomad AMR exome AF: 0.00281

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.00442

GnomAD4 exome AF: 0.00200 AC: 2929 AN: 1461738 Hom.: 99 Cov.: 32 AF XY: 0.00179 AC XY: 1301 AN XY: 727166

African (AFR) AF: 0.0682 AC: 2281 AN: 33470

American (AMR) AF: 0.00353 AC: 158 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5766

European-Non Finnish (NFE) AF: 0.000165 AC: 183 AN: 1111952

Other (OTH) AF: 0.00419 AC: 253 AN: 60384

GnomAD4 genome AF: 0.0183 AC: 2789 AN: 152270 Hom.: 67 Cov.: 32 AF XY: 0.0169 AC XY: 1258 AN XY: 74454

African (AFR) AF: 0.0641 AC: 2663 AN: 41542

American (AMR) AF: 0.00497 AC: 76 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68016

Other (OTH) AF: 0.0123 AC: 26 AN: 2110

Alfa AF: 0.0147 Hom.: 47

Bravo AF: 0.0207

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Werner syndrome (4)
-	-	2	not provided (2)
-	-	1	Wiskott-Aldrich syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.36
DANN	Benign	0.32
PhyloP100		-0.99
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: rs2230010; hg19: chr8-30938698;