rs2667590

Variant names:

• chr16-78497140-G-C
• rs2667590
• NM_016373.4:c.1056+64388G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-78497140-G-C
• chr16-78497140-G-T

Variant summary

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

The NM_016373.4(WWOX):​c.1056+64388G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.91 in 152,262 control chromosomes in the GnomAD database, including 63,554 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 0.91 (63554 hom., cov: 34)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0520
• Publications: 1 publications found

Genes affected

WWOX (HGNC:12799): (WW domain containing oxidoreductase) This gene encodes a member of the short-chain dehydrogenases/reductases (SDR) protein family. This gene spans the FRA16D common chromosomal fragile site and appears to function as a tumor suppressor gene. Expression of the encoded protein is able to induce apoptosis, while defects in this gene are associated with multiple types of cancer. Disruption of this gene is also associated with autosomal recessive spinocerebellar ataxia 12. Disruption of a similar gene in mouse results in impaired steroidogenesis, additionally suggesting a metabolic function for the protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

WWOX Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive spinocerebellar ataxia 12

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• developmental and epileptic encephalopathy, 28

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 46,XY partial gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000260733 (HGNC:58302):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.962 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WWOX	NM_016373.4	c.1056+64388G>C		intron_variant	Intron 8 of 8	ENST00000566780.6	NP_057457.1
WWOX	NM_001291997.2	c.717+64388G>C		intron_variant	Intron 7 of 7		NP_001278926.1
WWOX-AS2	XR_007065129.1	n.89-709C>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WWOX	ENST00000566780.6	c.1056+64388G>C		intron_variant	Intron 8 of 8	1	NM_016373.4	ENSP00000457230.1

Frequencies

GnomAD3 genomes AF: 0.910 AC: 138447 AN: 152144 Hom.: 63495 Cov.: 34

Gnomad AFR AF: 0.790

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.964

Gnomad ASJ AF: 0.939

Gnomad EAS AF: 0.838

Gnomad SAS AF: 0.820

Gnomad FIN AF: 0.980

Gnomad MID AF: 0.934

Gnomad NFE AF: 0.968

Gnomad OTH AF: 0.934

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

GnomAD4 genome AF: 0.910 AC: 138569 AN: 152262 Hom.: 63554 Cov.: 34 AF XY: 0.910 AC XY: 67752 AN XY: 74452

African (AFR) AF: 0.790 AC: 32796 AN: 41510

American (AMR) AF: 0.964 AC: 14761 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.939 AC: 3258 AN: 3470

East Asian (EAS) AF: 0.838 AC: 4333 AN: 5170

South Asian (SAS) AF: 0.821 AC: 3964 AN: 4826

European-Finnish (FIN) AF: 0.980 AC: 10401 AN: 10618

Middle Eastern (MID) AF: 0.935 AC: 275 AN: 294

European-Non Finnish (NFE) AF: 0.968 AC: 65893 AN: 68040

Other (OTH) AF: 0.934 AC: 1976 AN: 2116

Alfa AF: 0.938 Hom.: 7870

Bravo AF: 0.905

Asia WGS AF: 0.864 AC: 3007 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.59
DANN	Benign	0.43
PhyloP100		-0.052
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: rs2667590; hg19: chr16-78531037;