2-19911243-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001006657.2(WDR35):c.*2315G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 152,264 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (16 hom., cov: 33)
  • Exomes 𝑓: 0.042 (0 hom.)
• Consequence: WDR35 NM_001006657.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.295

Genes affected

WDR35 (HGNC:29250): (WD repeat domain 35) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. Two patients with Sensenbrenner syndrome / cranioectodermal dysplasia (CED) were identified with mutations in this gene, consistent with a possible ciliary function.[provided by RefSeq, Sep 2010]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-19911243-C-G is Benign according to our data. Variant chr2-19911243-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 895898.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency = 0.0625 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR35	NM_001006657.2	c.*2315G>C		3_prime_UTR_variant	28/28	ENST00000345530.8
WDR35	NM_020779.4	c.*2315G>C		3_prime_UTR_variant	27/27	ENST00000281405.9
WDR35	XM_011533007.3	c.*2315G>C		3_prime_UTR_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR35	ENST00000281405.9	c.*2315G>C		3_prime_UTR_variant	27/27	1	NM_020779.4	P3
WDR35	ENST00000345530.8	c.*2315G>C		3_prime_UTR_variant	28/28	1	NM_001006657.2	A1

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2084 AN: 152122 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.00736

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.0417 AC: 1 AN: 24 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 20

Gnomad4 AFR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0625

GnomAD4 genome AF: 0.0137 AC: 2082 AN: 152240 Hom.: 16 Cov.: 33 AF XY: 0.0132 AC XY: 982 AN XY: 74428

Gnomad4 AFR AF: 0.00325

Gnomad4 AMR AF: 0.0181

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00808

Gnomad4 FIN AF: 0.00736

Gnomad4 NFE AF: 0.0211

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0186 Hom.: 6

Bravo AF: 0.0128

Asia WGS AF: 0.00231 AC: 9 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cranioectodermal dysplasia 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Short-rib thoracic dysplasia 7 with or without polydactyly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	2.9
Dann	Benign	0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs72779355; hg19: chr2-20111004;