2-19989328-C-T

Variant names:

• chr2-19989328-C-T
• rs3731663
• NM_001006657.2:c.25-46G>A

Variant summary

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

The NM_020779.4(WDR35):​c.25-46G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 1,517,914 control chromosomes in the GnomAD database, including 211,941 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25761 hom., cov: 33)
  • Exomes 𝑓: 0.52 (186180 hom.)
• Consequence: WDR35 NM_020779.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.10
• Publications: 17 publications found

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]

WDR35 Gene-Disease associations (from GenCC):

• cranioectodermal dysplasia 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, G2P, Ambry Genetics
• short-rib thoracic dysplasia 7 with or without polydactyly

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• cranioectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Verma-Naumoff type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 2-19989328-C-T is Benign according to our data. Variant chr2-19989328-C-T is described in ClinVar as Benign. ClinVar VariationId is 256876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.714 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020779.4. 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
	WDR35	NM_001006657.2	MANE Plus Clinical	c.25-46G>A		intron	N/A	NP_001006658.1	Q9P2L0-1
	WDR35	NM_020779.4	MANE Select	c.25-46G>A		intron	N/A	NP_065830.2	Q9P2L0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR35	ENST00000345530.8	TSL:1 MANE Plus Clinical	c.25-46G>A		intron	N/A	ENSP00000314444.5	Q9P2L0-1
	WDR35	ENST00000281405.9	TSL:1 MANE Select	c.25-46G>A		intron	N/A	ENSP00000281405.5	Q9P2L0-2
	WDR35	ENST00000968993.1		c.25-46G>A		intron	N/A	ENSP00000639052.1

Frequencies

GnomAD3 genomes AF: 0.573 AC: 86980 AN: 151882 Hom.: 25715 Cov.: 33

Gnomad AFR AF: 0.721

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.547

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.666

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.489

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.498

Gnomad OTH AF: 0.548

GnomAD2 exomes AF: 0.541 AC: 135949 AN: 251180 AF XY: 0.540

Gnomad AFR exome AF: 0.723

Gnomad AMR exome AF: 0.525

Gnomad ASJ exome AF: 0.457

Gnomad EAS exome AF: 0.665

Gnomad FIN exome AF: 0.498

Gnomad NFE exome AF: 0.495

Gnomad OTH exome AF: 0.523

GnomAD4 exome AF: 0.518 AC: 707409 AN: 1365914 Hom.: 186180 Cov.: 21 AF XY: 0.520 AC XY: 356256 AN XY: 685080

African (AFR) AF: 0.733 AC: 23243 AN: 31704

American (AMR) AF: 0.523 AC: 23308 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 11770 AN: 25526

East Asian (EAS) AF: 0.713 AC: 27955 AN: 39208

South Asian (SAS) AF: 0.622 AC: 52386 AN: 84224

European-Finnish (FIN) AF: 0.494 AC: 26351 AN: 53322

Middle Eastern (MID) AF: 0.553 AC: 3079 AN: 5570

European-Non Finnish (NFE) AF: 0.497 AC: 509400 AN: 1024580

Other (OTH) AF: 0.523 AC: 29917 AN: 57196

GnomAD4 genome AF: 0.573 AC: 87086 AN: 152000 Hom.: 25761 Cov.: 33 AF XY: 0.574 AC XY: 42654 AN XY: 74282

African (AFR) AF: 0.721 AC: 29908 AN: 41468

American (AMR) AF: 0.547 AC: 8360 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1576 AN: 3466

East Asian (EAS) AF: 0.665 AC: 3435 AN: 5162

South Asian (SAS) AF: 0.622 AC: 3000 AN: 4824

European-Finnish (FIN) AF: 0.489 AC: 5157 AN: 10542

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.498 AC: 33812 AN: 67948

Other (OTH) AF: 0.554 AC: 1167 AN: 2108

Alfa AF: 0.513 Hom.: 35035

Bravo AF: 0.579

Asia WGS AF: 0.663 AC: 2303 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cranioectodermal dysplasia 2 (1)
-	-	1	not specified (1)
-	-	1	Short-rib thoracic dysplasia 7 with or without polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.090
DANN	Benign	0.70
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs3731663; hg19: chr2-20189089; COSMIC: COSV55608311; COSMIC: COSV55608311;