rs730882206

Positions:

• chr17-1725804-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_001163809.2(WDR81):​c.845G>A​(p.Gly282Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: WDR81 NM_001163809.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:4
• Conservation: PhyloP100: 9.90

Genes affected

WDR81 (HGNC:26600): (WD repeat domain 81) This gene encodes a multi-domain transmembrane protein which is predominantly expressed in the brain and is thought to play a role in endolysosomal trafficking. Mutations in this gene are associated with an autosomal recessive form of a syndrome exhibiting cerebellar ataxia, cognitive disability, and disequilibrium (CAMRQ2). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant 17-1725804-G-A is Pathogenic according to our data. Variant chr17-1725804-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183290.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-1725804-G-A is described in Lovd as [Pathogenic]. Variant chr17-1725804-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR81	NM_001163809.2	c.845G>A	p.Gly282Glu	missense_variant	1/10	ENST00000409644.6	NP_001157281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR81	ENST00000409644.6	c.845G>A	p.Gly282Glu	missense_variant	1/10	1	NM_001163809.2	ENSP00000386609	P1
	ENST00000576540.1	n.403C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 80

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, single submitter

Submissions by phenotype

Hydranencephaly;C0410916:Neonatal death;CN228280:Severe brain malformation;CN228281:Severe cerebellar hypoplasia Pathogenic:1

Likely pathogenic, flagged submission

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Dec 01, 2014

- -

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 17, 2024

- -

not provided Pathogenic:1

Likely pathogenic, flagged submission

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

-

- -

Hydrocephalus, congenital, 3, with brain anomalies Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.97
MutPred		0.66		Gain of helix (P = 0.0496);
MVP		0.60
MPC		1.4
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.67
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs730882206; hg19: chr17-1629098;