17-1730810-C-T

Variant names:

• chr17-1730810-C-T
• rs12150338
• ENST00000446363.5:c.-253C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000446363.5(WDR81):​c.-253C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0993 in 1,612,388 control chromosomes in the GnomAD database, including 8,864 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (805 hom., cov: 33)
  • Exomes 𝑓: 0.10 (8059 hom.)
• Consequence: WDR81 ENST00000446363.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.79
• Publications: 27 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

WDR81-AS1 (HGNC:58142):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 17-1730810-C-T is Benign according to our data. Variant chr17-1730810-C-T is described in ClinVar as Benign. ClinVar VariationId is 130738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000446363.5. 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.3831C>T	p.Ala1277Ala	synonymous	Exon 3 of 10	NP_001157281.1
	WDR81	NM_152348.4		c.678C>T	p.Ala226Ala	synonymous	Exon 4 of 11	NP_689561.2
	WDR81	NM_001163673.2		c.222C>T	p.Ala74Ala	synonymous	Exon 3 of 10	NP_001157145.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR81	ENST00000446363.5	TSL:1	c.-253C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	ENSP00000401560.1
	WDR81	ENST00000409644.6	TSL:1 MANE Select	c.3831C>T	p.Ala1277Ala	synonymous	Exon 3 of 10	ENSP00000386609.1
	WDR81	ENST00000446363.5	TSL:1	c.-253C>T		5_prime_UTR	Exon 2 of 9	ENSP00000401560.1

Frequencies

GnomAD3 genomes AF: 0.0937 AC: 14258 AN: 152138 Hom.: 803 Cov.: 33

Gnomad AFR AF: 0.0676

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0687

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0882

Gnomad OTH AF: 0.103

GnomAD2 exomes AF: 0.119 AC: 29305 AN: 247274 AF XY: 0.118

Gnomad AFR exome AF: 0.0655

Gnomad AMR exome AF: 0.219

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.132

Gnomad FIN exome AF: 0.0693

Gnomad NFE exome AF: 0.0910

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.0999 AC: 145871 AN: 1460132 Hom.: 8059 Cov.: 34 AF XY: 0.101 AC XY: 73659 AN XY: 726392

African (AFR) AF: 0.0675 AC: 2261 AN: 33474

American (AMR) AF: 0.212 AC: 9457 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 3296 AN: 26128

East Asian (EAS) AF: 0.143 AC: 5668 AN: 39694

South Asian (SAS) AF: 0.160 AC: 13812 AN: 86254

European-Finnish (FIN) AF: 0.0694 AC: 3594 AN: 51810

Middle Eastern (MID) AF: 0.150 AC: 865 AN: 5768

European-Non Finnish (NFE) AF: 0.0905 AC: 100610 AN: 1111930

Other (OTH) AF: 0.104 AC: 6308 AN: 60366

GnomAD4 genome AF: 0.0937 AC: 14259 AN: 152256 Hom.: 805 Cov.: 33 AF XY: 0.0976 AC XY: 7266 AN XY: 74460

African (AFR) AF: 0.0674 AC: 2803 AN: 41574

American (AMR) AF: 0.162 AC: 2484 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 409 AN: 3470

East Asian (EAS) AF: 0.137 AC: 707 AN: 5158

South Asian (SAS) AF: 0.157 AC: 758 AN: 4828

European-Finnish (FIN) AF: 0.0687 AC: 730 AN: 10626

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.0882 AC: 5995 AN: 67988

Other (OTH) AF: 0.102 AC: 215 AN: 2112

Alfa AF: 0.0922 Hom.: 2503

Bravo AF: 0.0990

Asia WGS AF: 0.131 AC: 454 AN: 3478

EpiCase AF: 0.0960

EpiControl AF: 0.0958

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.16
DANN	Benign	0.82
PhyloP100		-4.8
Mutation Taster		=298/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12150338; hg19: chr17-1634104; COSMIC: COSV100488722; COSMIC: COSV100488722;