NM_001006657.2:c.2599G>T

Variant names:

• chr2-19933493-C-A
• rs149667250
• NM_001006657.2:c.2599G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001006657.2(WDR35):​c.2599G>T​(p.Val867Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00159 in 1,613,700 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V867V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (82 hom.)
• Consequence: WDR35 NM_001006657.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.70
• Publications: 1 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 (MetaRNN=0.004893422).
• BP6: Variant 2-19933493-C-A is Benign according to our data. Variant chr2-19933493-C-A is described in ClinVar as Benign. ClinVar VariationId is 93463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00186 (283/152300) while in subpopulation AMR AF = 0.0171 (261/15288). AF 95% confidence interval is 0.0154. There are 3 homozygotes in GnomAd4. There are 153 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001006657.2. 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
	WDR35	NM_001006657.2	MANE Plus Clinical	c.2599G>T	p.Val867Phe	missense	Exon 23 of 28	NP_001006658.1	Q9P2L0-1
	WDR35	NM_020779.4	MANE Select	c.2566G>T	p.Val856Phe	missense	Exon 22 of 27	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.2599G>T	p.Val867Phe	missense	Exon 23 of 28	ENSP00000314444.5	Q9P2L0-1
	WDR35	ENST00000281405.9	TSL:1 MANE Select	c.2566G>T	p.Val856Phe	missense	Exon 22 of 27	ENSP00000281405.5	Q9P2L0-2
	WDR35	ENST00000968993.1		c.2494G>T	p.Val832Phe	missense	Exon 21 of 26	ENSP00000639052.1

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 281 AN: 152182 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0170

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: 0.00

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00767 AC: 1926 AN: 251120 AF XY: 0.00581

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0548

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00156 AC: 2276 AN: 1461400 Hom.: 82 Cov.: 32 AF XY: 0.00129 AC XY: 938 AN XY: 727030

African (AFR) AF: 0.000239 AC: 8 AN: 33470

American (AMR) AF: 0.0490 AC: 2191 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111880

Other (OTH) AF: 0.00111 AC: 67 AN: 60388

GnomAD4 genome AF: 0.00186 AC: 283 AN: 152300 Hom.: 3 Cov.: 32 AF XY: 0.00205 AC XY: 153 AN XY: 74472

African (AFR) AF: 0.000409 AC: 17 AN: 41564

American (AMR) AF: 0.0171 AC: 261 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000456 Hom.: 2

Bravo AF: 0.00452

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00631 AC: 766

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	Cranioectodermal dysplasia 2;C3279792:Short-rib thoracic dysplasia 7 with or without polydactyly (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
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.043
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.098
Sift	Benign	0.27	T
Sift4G	Benign	0.23	T
Polyphen		0.0070	B
Vest4		0.61
MVP		0.18
MPC		0.63
ClinPred		0.029	T
GERP RS		3.4
Varity_R		0.17
gMVP		0.62
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs149667250; hg19: chr2-20133254;