2-19933493-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020779.4(WDR35):​c.2566G>C​(p.Val856Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: WDR35 NM_020779.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.70

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17482999).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR35	NM_001006657.2	c.2599G>C	p.Val867Leu	missense_variant	Exon 23 of 28	ENST00000345530.8	NP_001006658.1
WDR35	NM_020779.4	c.2566G>C	p.Val856Leu	missense_variant	Exon 22 of 27	ENST00000281405.9	NP_065830.2
WDR35	XM_011533007.3	c.1294G>C	p.Val432Leu	missense_variant	Exon 12 of 17		XP_011531309.1
WDR35	XR_426989.4	n.2656G>C		non_coding_transcript_exon_variant	Exon 22 of 25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR35	ENST00000345530.8	c.2599G>C	p.Val867Leu	missense_variant	Exon 23 of 28	1	NM_001006657.2	ENSP00000314444.5
WDR35	ENST00000281405.9	c.2566G>C	p.Val856Leu	missense_variant	Exon 22 of 27	1	NM_020779.4	ENSP00000281405.5
WDR35	ENST00000414212.5	n.2603G>C		non_coding_transcript_exon_variant	Exon 23 of 28	5		ENSP00000390802.1
WDR35	ENST00000445063.5	n.*1271+1978G>C		intron_variant	Intron 15 of 17	2		ENSP00000390105.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251120 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461404 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727030

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.026	.;T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.059
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	.;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.061
Sift	Benign	0.20	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.035	B;B
Vest4		0.18
MutPred		0.55		.;Loss of helix (P = 0.1706);
MVP		0.16
MPC		0.54
ClinPred		0.68	D
GERP RS		3.4
Varity_R		0.11
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs149667250; hg19: chr2-20133254;