rs2230721

Variant names:

• chr4-6302117-G-A
• rs2230721
• NM_006005.3:c.2322G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006005.3(WFS1):​c.2322G>A​(p.Lys774Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0734 in 1,612,924 control chromosomes in the GnomAD database, including 4,881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (452 hom., cov: 34)
  • Exomes 𝑓: 0.074 (4429 hom.)
• Consequence: WFS1 NM_006005.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.73

Genes affected

WFS1 (HGNC:12762): (wolframin ER transmembrane glycoprotein) This gene encodes a transmembrane protein, which is located primarily in the endoplasmic reticulum and ubiquitously expressed with highest levels in brain, pancreas, heart, and insulinoma beta-cell lines. Mutations in this gene are associated with Wolfram syndrome, also called DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness), an autosomal recessive disorder. The disease affects the brain and central nervous system. Mutations in this gene can also cause autosomal dominant deafness 6 (DFNA6), also known as DFNA14 or DFNA38. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2009]

ENSG00000286176 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 4-6302117-G-A is Benign according to our data. Variant chr4-6302117-G-A is described in ClinVar as [Benign]. Clinvar id is 45452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-6302117-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WFS1	NM_006005.3	c.2322G>A	p.Lys774Lys	synonymous_variant	Exon 8 of 8	ENST00000226760.5	NP_005996.2
WFS1	NM_001145853.1	c.2322G>A	p.Lys774Lys	synonymous_variant	Exon 8 of 8		NP_001139325.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5	c.2322G>A	p.Lys774Lys	synonymous_variant	Exon 8 of 8	1	NM_006005.3	ENSP00000226760.1

Frequencies

GnomAD3 genomes AF: 0.0687 AC: 10461 AN: 152228 Hom.: 452 Cov.: 34

Gnomad AFR AF: 0.0769

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.0512

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.0238

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0735

Gnomad OTH AF: 0.0635

GnomAD3 exomes AF: 0.0634 AC: 15694 AN: 247402 Hom.: 626 AF XY: 0.0667 AC XY: 8969 AN XY: 134566

Gnomad AFR exome AF: 0.0773

Gnomad AMR exome AF: 0.0339

Gnomad ASJ exome AF: 0.0912

Gnomad EAS exome AF: 0.000494

Gnomad SAS exome AF: 0.108

Gnomad FIN exome AF: 0.0283

Gnomad NFE exome AF: 0.0730

Gnomad OTH exome AF: 0.0637

GnomAD4 exome AF: 0.0739 AC: 107885 AN: 1460578 Hom.: 4429 Cov.: 100 AF XY: 0.0749 AC XY: 54398 AN XY: 726582

Gnomad4 AFR exome AF: 0.0780

Gnomad4 AMR exome AF: 0.0355

Gnomad4 ASJ exome AF: 0.0916

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.0293

Gnomad4 NFE exome AF: 0.0769

Gnomad4 OTH exome AF: 0.0719

GnomAD4 genome AF: 0.0687 AC: 10462 AN: 152346 Hom.: 452 Cov.: 34 AF XY: 0.0668 AC XY: 4976 AN XY: 74504

Gnomad4 AFR AF: 0.0767

Gnomad4 AMR AF: 0.0511

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.111

Gnomad4 FIN AF: 0.0238

Gnomad4 NFE AF: 0.0735

Gnomad4 OTH AF: 0.0643

Alfa AF: 0.0731 Hom.: 364

Bravo AF: 0.0697

Asia WGS AF: 0.0700 AC: 241 AN: 3478

EpiCase AF: 0.0770

EpiControl AF: 0.0770

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

May 22, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lys774Lys in Exon 08 of WFS1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 7.3% (273/3734) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2230721). -

Nov 20, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

WFS1-Related Spectrum Disorders Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal dominant nonsyndromic hearing loss 6 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Wolfram syndrome 1 Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Potent mutations in WFS1 gene are associated with Wolfram's syndrome, an autosomal recessive condition, which cause diabetes mellitus, diabetes insipidus, deafness and optic atrophy.However no sufficient evidence is found to ascertain the role of this particular variant rs2230721 yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	5.6
DANN	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs2230721; hg19: chr4-6303844;