17-1725300-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001163809.2(WDR81):​c.341G>A​(p.Arg114Lys) 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. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign 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. 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14007026).

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>A	p.Arg114Lys	missense	Exon 1 of 10	NP_001157281.1	Q562E7-1
	WDR81	NM_152348.4		c.-123-2690G>A		intron	N/A	NP_689561.2	Q562E7-3
	WDR81	NM_001163673.2		c.59-5080G>A		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>A	p.Arg114Lys	missense	Exon 1 of 10	ENSP00000386609.1	Q562E7-1
	WDR81	ENST00000446363.5	TSL:1	c.-308-5455G>A		intron	N/A	ENSP00000401560.1	E9PDG3
	WDR81	ENST00000309182.9	TSL:2	c.-123-2690G>A		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: 0.00 AC: 0 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: 0.00 AC: 0 AN: 45546

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

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078922

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

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Benign	0.85
DEOGEN2	Benign	0.013	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.063
Sift	Benign	0.90	T
Sift4G	Benign	0.27	T
Vest4		0.19
MutPred		0.30		Gain of methylation at R114 (P = 0.0769)
MVP		0.40
MPC		0.43
ClinPred		0.27	T
GERP RS		3.7
Varity_R		0.14
gMVP		0.17

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;