17-1725229-C-T

Variant names:

• chr17-1725229-C-T
• rs74639548
• NM_001163809.2:c.270C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001163809.2(WDR81):​c.270C>T​(p.Leu90Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000848 in 1,540,636 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (6 hom.)
• Consequence: WDR81 NM_001163809.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.444
• Publications: 1 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 17-1725229-C-T is Benign according to our data. Variant chr17-1725229-C-T is described in ClinVar as Benign. ClinVar VariationId is 783746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.444 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0044 (671/152382) while in subpopulation AFR AF = 0.0153 (638/41596). AF 95% confidence interval is 0.0144. There are 6 homozygotes in GnomAd4. There are 321 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.270C>T	p.Leu90Leu	synonymous	Exon 1 of 10	NP_001157281.1	Q562E7-1
	WDR81	NM_152348.4		c.-123-2761C>T		intron	N/A	NP_689561.2	Q562E7-3
	WDR81	NM_001163673.2		c.59-5151C>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.270C>T	p.Leu90Leu	synonymous	Exon 1 of 10	ENSP00000386609.1	Q562E7-1
	WDR81	ENST00000446363.5	TSL:1	c.-308-5526C>T		intron	N/A	ENSP00000401560.1	E9PDG3
	WDR81	ENST00000309182.9	TSL:2	c.-123-2761C>T		intron	N/A	ENSP00000312074.5	Q562E7-3

Frequencies

GnomAD3 genomes AF: 0.00441 AC: 672 AN: 152264 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.000888 AC: 125 AN: 140820 AF XY: 0.000719

Gnomad AFR exome AF: 0.0166

Gnomad AMR exome AF: 0.000448

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000360

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000458 AC: 636 AN: 1388254 Hom.: 6 Cov.: 75 AF XY: 0.000382 AC XY: 262 AN XY: 685172

African (AFR) AF: 0.0167 AC: 529 AN: 31592

American (AMR) AF: 0.000476 AC: 17 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.0000379 AC: 3 AN: 79230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38380

Middle Eastern (MID) AF: 0.000352 AC: 2 AN: 5686

European-Non Finnish (NFE) AF: 0.0000278 AC: 30 AN: 1078844

Other (OTH) AF: 0.000950 AC: 55 AN: 57914

GnomAD4 genome AF: 0.00440 AC: 671 AN: 152382 Hom.: 6 Cov.: 33 AF XY: 0.00431 AC XY: 321 AN XY: 74520

African (AFR) AF: 0.0153 AC: 638 AN: 41596

American (AMR) AF: 0.00137 AC: 21 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68034

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.000606 Hom.: 1

Bravo AF: 0.00535

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.6
DANN	Benign	0.93
PhyloP100		-0.44
Mutation Taster		=100/0	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: rs74639548; hg19: chr17-1628523;