19-36055107-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001083961.2(WDR62):c.136A>C(p.Thr46Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T46T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.65

Genes affected

WDR62 (HGNC:24502): (WD repeat domain 62) This gene is proposed to play a role in cerebral cortical development. Mutations in this gene have been associated with microencephaly, cortical malformations, and cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a modified_residue Phosphothreonine (size 0) in uniprot entity WDR62_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33696288).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR62	NM_001083961.2	c.136A>C	p.Thr46Pro	missense_variant	1/32	ENST00000401500.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR62	ENST00000401500.7	c.136A>C	p.Thr46Pro	missense_variant	1/32	1	NM_001083961.2	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2021

The c.136A>C (p.T46P) alteration is located in exon 1 (coding exon 1) of the WDR62 gene. This alteration results from a A to C substitution at nucleotide position 136, causing the threonine (T) at amino acid position 46 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.59	T;T;T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	0.83	D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.86	N;N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.017	D;D;T
Sift4G	Benign	0.073	T;T;D
Polyphen		0.99	D;D;.
Vest4		0.49
MutPred		0.33		Loss of phosphorylation at T46 (P = 0.005);Loss of phosphorylation at T46 (P = 0.005);.;
MVP		0.75
MPC		0.92
ClinPred		0.91	D
GERP RS		3.1
Varity_R		0.43
gMVP		0.41

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-36546009;