2-74422272-C-T

Variant names:

• chr2-74422272-C-T
• rs374998217
• NM_032118.4:c.119C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032118.4(WDR54):​c.119C>T​(p.Pro40Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,866 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WDR54 NM_032118.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.44
• Publications: 0 publications found

Genes affected

WDR54 (HGNC:25770): (WD repeat domain 54) Enables protein homodimerization activity. Involved in negative regulation of receptor internalization; regulation of MAPK cascade; and regulation of epidermal growth factor receptor signaling pathway. Located in vesicle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19806841).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032118.4. 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
	WDR54	NM_032118.4	MANE Select	c.119C>T	p.Pro40Leu	missense	Exon 2 of 10	NP_115494.1	Q9H977-1
	WDR54	NM_001320823.2		c.164C>T	p.Pro55Leu	missense	Exon 2 of 10	NP_001307752.1	Q9H977-4
	WDR54	NM_001320824.2		c.119C>T	p.Pro40Leu	missense	Exon 2 of 10	NP_001307753.1	Q9H977-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR54	ENST00000348227.4	TSL:1 MANE Select	c.119C>T	p.Pro40Leu	missense	Exon 2 of 10	ENSP00000006526.6	Q9H977-1
	WDR54	ENST00000465134.5	TSL:1	n.529C>T		non_coding_transcript_exon	Exon 1 of 7
	WDR54	ENST00000861017.1		c.119C>T	p.Pro40Leu	missense	Exon 2 of 10	ENSP00000531076.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461866 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.0065
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.4
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.085
Sift	Uncertain	0.028	D
Sift4G	Benign	0.079	T
Polyphen		0.26	B
Vest4		0.57
MutPred		0.50		Gain of catalytic residue at P40 (P = 0.0026)
MVP		0.42
MPC		0.24
ClinPred		0.88	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.12
gMVP		0.45
Mutation Taster		=87/13	polymorphism

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: rs374998217; hg19: chr2-74649399;