17-1725300-G-T

Variant names:

• chr17-1725300-G-T
• rs922125870
• NM_001163809.2:c.341G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001163809.2(WDR81):​c.341G>T​(p.Arg114Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,395,582 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R114T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: WDR81 NM_001163809.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.66
• 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: Labcorp Genetics (formerly Invitae), G2P
• cerebellar ataxia, intellectual disability, and dysequilibrium

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR81	NM_001163809.2	MANE Select	c.341G>T	p.Arg114Ile	missense	Exon 1 of 10	NP_001157281.1	Q562E7-1
	WDR81	NM_152348.4		c.-123-2690G>T		intron	N/A	NP_689561.2	Q562E7-3
	WDR81	NM_001163673.2		c.59-5080G>T		intron	N/A	NP_001157145.1	Q562E7-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR81	ENST00000409644.6	TSL:1 MANE Select	c.341G>T	p.Arg114Ile	missense	Exon 1 of 10	ENSP00000386609.1	Q562E7-1
	WDR81	ENST00000446363.5	TSL:1	c.-308-5455G>T		intron	N/A	ENSP00000401560.1	E9PDG3
	WDR81	ENST00000309182.9	TSL:2	c.-123-2690G>T		intron	N/A	ENSP00000312074.5	Q562E7-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1395582 Hom.: 0 Cov.: 74 AF XY: 0.00 AC XY: 0 AN XY: 688396

African (AFR) AF: 0.0000316 AC: 1 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79228

European-Finnish (FIN) AF: 0.0000220 AC: 1 AN: 45546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078922

Other (OTH) AF: 0.00 AC: 0 AN: 57970

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.032	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.16
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.0030	D
Vest4		0.55
MutPred		0.52		Loss of disorder (P = 0.0144)
MVP		0.59
MPC		1.6
ClinPred		0.78	D
GERP RS		3.7
Varity_R		0.15
gMVP		0.33
Mutation Taster		=80/20	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: rs922125870; hg19: chr17-1628594;