12-118043202-C-T

Variant names:

• chr12-118043202-C-T
• rs113350351
• NM_018639.5:c.358G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_018639.5(WSB2):​c.358G>A​(p.Asp120Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0039 in 1,614,234 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0033 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (28 hom.)
• Consequence: WSB2 NM_018639.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.89
• Publications: 8 publications found

Genes affected

WSB2 (HGNC:19222): (WD repeat and SOCS box containing 2) This gene encodes a member of the WD-protein subfamily. The encoded protein contains five WD-repeats spanning most of the protein and an SOCS box in the C-terminus. The SOCS box may act as a bridge between specific substrate-binding domains and E3 ubiquitin protein ligases. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2013]

WSB2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037802756).
• BP6: Variant 12-118043202-C-T is Benign according to our data. Variant chr12-118043202-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2643380.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00396 (5792/1461894) while in subpopulation MID AF = 0.0182 (105/5768). AF 95% confidence interval is 0.0154. There are 28 homozygotes in GnomAdExome4. There are 2948 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 28 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018639.5. 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
	WSB2	NM_018639.5	MANE Select	c.358G>A	p.Asp120Asn	missense	Exon 3 of 9	NP_061109.1	Q9NYS7-1
	WSB2	NM_001278557.1		c.409G>A	p.Asp137Asn	missense	Exon 3 of 9	NP_001265486.1	Q9NYS7-2
	WSB2	NM_001278558.2		c.-71-4814G>A		intron	N/A	NP_001265487.1	Q9NYS7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WSB2	ENST00000315436.8	TSL:1 MANE Select	c.358G>A	p.Asp120Asn	missense	Exon 3 of 9	ENSP00000319474.3	Q9NYS7-1
	WSB2	ENST00000535496.5	TSL:1	c.364G>A	p.Asp122Asn	missense	Exon 2 of 8	ENSP00000439450.1	F5H280
	WSB2	ENST00000540129.5	TSL:1	n.399G>A		non_coding_transcript_exon	Exon 3 of 7

Frequencies

GnomAD3 genomes AF: 0.00328 AC: 499 AN: 152222 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00494

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.00358 AC: 900 AN: 251218 AF XY: 0.00410

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00559

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00396 AC: 5792 AN: 1461894 Hom.: 28 Cov.: 32 AF XY: 0.00405 AC XY: 2948 AN XY: 727248

African (AFR) AF: 0.00108 AC: 36 AN: 33480

American (AMR) AF: 0.00241 AC: 108 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00142 AC: 37 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00464 AC: 400 AN: 86258

European-Finnish (FIN) AF: 0.000374 AC: 20 AN: 53420

Middle Eastern (MID) AF: 0.0182 AC: 105 AN: 5768

European-Non Finnish (NFE) AF: 0.00434 AC: 4822 AN: 1112012

Other (OTH) AF: 0.00435 AC: 263 AN: 60396

GnomAD4 genome AF: 0.00326 AC: 496 AN: 152340 Hom.: 1 Cov.: 32 AF XY: 0.00313 AC XY: 233 AN XY: 74504

African (AFR) AF: 0.000866 AC: 36 AN: 41588

American (AMR) AF: 0.00340 AC: 52 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00494 AC: 336 AN: 68030

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00421 Hom.: 2

Bravo AF: 0.00332

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00382 AC: 464

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00769

EpiControl AF: 0.00901

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0040	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.070
Sift	Benign	0.25	T
Sift4G	Benign	0.49	T
Polyphen		0.0010	B
Vest4		0.23
MVP		0.10
MPC		0.60
ClinPred		0.027	T
GERP RS		5.1
Varity_R		0.045
gMVP		0.24
Mutation Taster		=99/1	polymorphism

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: rs113350351; hg19: chr12-118481007; COSMIC: COSV59573495; COSMIC: COSV59573495;