NM_001163809.2:c.121G>C

Variant names:

• chr17-1725080-G-C
• NM_001163809.2:c.121G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001163809.2(WDR81):​c.121G>C​(p.Asp41His) variant causes a missense change. The variant allele was found at a frequency of 0.000000747 in 1,339,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: WDR81 NM_001163809.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.61
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30482867).

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.121G>C	p.Asp41His	missense	Exon 1 of 10	NP_001157281.1	Q562E7-1
	WDR81	NM_152348.4		c.-123-2910G>C		intron	N/A	NP_689561.2	Q562E7-3
	WDR81	NM_001163673.2		c.59-5300G>C		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.121G>C	p.Asp41His	missense	Exon 1 of 10	ENSP00000386609.1	Q562E7-1
	WDR81	ENST00000446363.5	TSL:1	c.-308-5675G>C		intron	N/A	ENSP00000401560.1	E9PDG3
	WDR81	ENST00000309182.9	TSL:2	c.-123-2910G>C		intron	N/A	ENSP00000312074.5	Q562E7-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.47e-7 AC: 1 AN: 1339544 Hom.: 0 Cov.: 74 AF XY: 0.00000153 AC XY: 1 AN XY: 654856

African (AFR) AF: 0.0000329 AC: 1 AN: 30410

American (AMR) AF: 0.00 AC: 0 AN: 29706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21756

East Asian (EAS) AF: 0.00 AC: 0 AN: 35170

South Asian (SAS) AF: 0.00 AC: 0 AN: 72260

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5370

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1052392

Other (OTH) AF: 0.00 AC: 0 AN: 55596

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.049	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.81	L
PhyloP100		5.6
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.093
Sift	Benign	0.048	D
Sift4G	Uncertain	0.0080	D
Vest4		0.36
MutPred		0.32		Loss of stability (P = 0.1222)
MVP		0.73
MPC		1.3
ClinPred		0.96	D
GERP RS		3.9
PromoterAI		-0.12	Neutral
Varity_R		0.15
gMVP		0.47
Mutation Taster		=63/37	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

hg19: chr17-1628374;