rs2548861

Variant names:

• chr16-78624496-T-G
• rs2548861
• NM_016373.4:c.1056+191744T>G

Your query was ambiguous. Multiple possible variants found:

• chr16-78624496-T-G
• chr16-78624496-T-C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_016373.4(WWOX):​c.1056+191744T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 152,036 control chromosomes in the GnomAD database, including 22,006 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.52 (22006 hom., cov: 32)
• Consequence: WWOX NM_016373.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.74
• Publications: 17 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P
• developmental and epileptic encephalopathy, 28

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), 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

ENSG00000288821 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 16-78624496-T-G is Benign according to our data. Variant chr16-78624496-T-G is described in ClinVar as Benign. ClinVar VariationId is 540240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.617 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016373.4. 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
	WWOX	NM_016373.4	MANE Select	c.1056+191744T>G		intron	N/A	NP_057457.1	Q9NZC7-1
	WWOX	NM_001291997.2		c.717+191744T>G		intron	N/A	NP_001278926.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WWOX	ENST00000566780.6	TSL:1 MANE Select	c.1056+191744T>G		intron	N/A	ENSP00000457230.1	Q9NZC7-1
	WWOX	ENST00000408984.7	TSL:1	c.1057-66746T>G		intron	N/A	ENSP00000386161.3	Q9NZC7-2
	WWOX	ENST00000402655.6	TSL:1	c.409+509342T>G		intron	N/A	ENSP00000384238.2	Q9NZC7-6

Frequencies

GnomAD3 genomes AF: 0.524 AC: 79641 AN: 151918 Hom.: 21998 Cov.: 32

Gnomad AFR AF: 0.339

Gnomad AMI AF: 0.556

Gnomad AMR AF: 0.616

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.635

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.605

Gnomad OTH AF: 0.566

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

GnomAD4 genome AF: 0.524 AC: 79680 AN: 152036 Hom.: 22006 Cov.: 32 AF XY: 0.521 AC XY: 38717 AN XY: 74288

African (AFR) AF: 0.339 AC: 14070 AN: 41470

American (AMR) AF: 0.616 AC: 9414 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2155 AN: 3464

East Asian (EAS) AF: 0.635 AC: 3272 AN: 5152

South Asian (SAS) AF: 0.534 AC: 2569 AN: 4814

European-Finnish (FIN) AF: 0.488 AC: 5156 AN: 10562

Middle Eastern (MID) AF: 0.627 AC: 183 AN: 292

European-Non Finnish (NFE) AF: 0.605 AC: 41159 AN: 67976

Other (OTH) AF: 0.566 AC: 1197 AN: 2114

Alfa AF: 0.583 Hom.: 105452

Bravo AF: 0.528

Asia WGS AF: 0.521 AC: 1811 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive spinocerebellar ataxia 12;C3463992:Developmental and epileptic encephalopathy, 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	15
DANN	Benign	0.69
PhyloP100		1.7
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: rs2548861; hg19: chr16-78658393;