17-1735723-G-C

Variant names:

• chr17-1735723-G-C
• rs115714169
• NM_001163809.2:c.5325+6G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001163809.2(WDR81):​c.5325+6G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,609,330 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (16 hom.)
• Consequence: WDR81 NM_001163809.2 splice_region, intron
• Scores: Splicing: ADA: 0.00008914
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.30

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]

ENSG00000262791 (HGNC:58142):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-1735723-G-C is Benign according to our data. Variant chr17-1735723-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 377010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-1735723-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00839 (1277/152290) while in subpopulation AFR AF= 0.0285 (1186/41554). AF 95% confidence interval is 0.0272. There are 15 homozygotes in gnomad4. There are 620 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR81	NM_001163809.2	c.5325+6G>C		splice_region_variant, intron_variant	Intron 8 of 9	ENST00000409644.6	NP_001157281.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR81	ENST00000409644.6	c.5325+6G>C		splice_region_variant, intron_variant	Intron 8 of 9	1	NM_001163809.2	ENSP00000386609.1

Frequencies

GnomAD3 genomes AF: 0.00839 AC: 1276 AN: 152174 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00484

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00215 AC: 524 AN: 244254 Hom.: 9 AF XY: 0.00163 AC XY: 216 AN XY: 132612

Gnomad AFR exome AF: 0.0289

Gnomad AMR exome AF: 0.00143

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000547

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.000804 AC: 1171 AN: 1457040 Hom.: 16 Cov.: 31 AF XY: 0.000647 AC XY: 469 AN XY: 724704

Gnomad4 AFR exome AF: 0.0282

Gnomad4 AMR exome AF: 0.00191

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00839 AC: 1277 AN: 152290 Hom.: 15 Cov.: 32 AF XY: 0.00832 AC XY: 620 AN XY: 74480

Gnomad4 AFR AF: 0.0285

Gnomad4 AMR AF: 0.00484

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000920 Hom.: 0

Bravo AF: 0.00923

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jan 12, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	9.5
DANN	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000089
dbscSNV1_RF	Benign	0.0040
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

Publications

LitVar

Other links and lift over

dbSNP: rs115714169; hg19: chr17-1639017;