chr17-1725804-G-C

Variant names:

• chr17-1725804-G-C
• rs730882206
• NM_001163809.2:c.845G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_001163809.2(WDR81):​c.845G>C​(p.Gly282Ala) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G282E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: WDR81 NM_001163809.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.90
• Publications: 0 publications found

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]

WDR81 Gene-Disease associations (from GenCC):

• cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• cerebellar ataxia, intellectual disability, and dysequilibrium

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000262791 (HGNC:58142):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-1725804-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 183290.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001163809.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR81	NM_001163809.2	MANE Select	c.845G>C	p.Gly282Ala	missense	Exon 1 of 10	NP_001157281.1
	WDR81	NM_152348.4		c.-123-2186G>C		intron	N/A	NP_689561.2
	WDR81	NM_001163673.2		c.59-4576G>C		intron	N/A	NP_001157145.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR81	ENST00000409644.6	TSL:1 MANE Select	c.845G>C	p.Gly282Ala	missense	Exon 1 of 10	ENSP00000386609.1
	WDR81	ENST00000446363.5	TSL:1	c.-308-4951G>C		intron	N/A	ENSP00000401560.1
	ENSG00000262791	ENST00000576540.1	TSL:3	n.403C>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 80

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.84
MutPred		0.47		Gain of helix (P = 0.0325)
MVP		0.47
MPC		1.3
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.57
gMVP		0.76

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: rs730882206; hg19: chr17-1629098;