17-1725027-C-T

Position:

• chr17-1725027-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001163809.2(WDR81):​c.68C>T​(p.Pro23Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000304 in 1,316,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: WDR81 NM_001163809.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12338227).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR81	NM_001163809.2	c.68C>T	p.Pro23Leu	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.68C>T	p.Pro23Leu	missense_variant	1/10	1	NM_001163809.2	ENSP00000386609.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000304 AC: 4 AN: 1316772 Hom.: 0 Cov.: 75 AF XY: 0.00000156 AC XY: 1 AN XY: 642952

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000287

Gnomad4 OTH exome AF: 0.0000184

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2024

The c.68C>T (p.P23L) alteration is located in exon 1 (coding exon 1) of the WDR81 gene. This alteration results from a C to T substitution at nucleotide position 68, causing the proline (P) at amino acid position 23 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Benign	0.86
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.55	N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.13
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0	D
Vest4		0.084
MutPred		0.20		Loss of glycosylation at P23 (P = 0.0079);
MVP		0.46
MPC		0.40
ClinPred		0.18	T
GERP RS		4.1
Varity_R		0.075
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs373264779; hg19: chr17-1628321;