19-36055092-T-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001083961.2(WDR62):c.121T>A(p.Cys41Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000202 in 1,605,338 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.98

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.010456711).
• BP6: Variant 19-36055092-T-A is Benign according to our data. Variant chr19-36055092-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 890931.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR62	NM_001083961.2	c.121T>A	p.Cys41Ser	missense_variant	1/32	ENST00000401500.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR62	ENST00000401500.7	c.121T>A	p.Cys41Ser	missense_variant	1/32	1	NM_001083961.2	P4

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 151932 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000349 AC: 79 AN: 226466 Hom.: 0 AF XY: 0.000360 AC XY: 45 AN XY: 125004

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00688

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000120

Gnomad OTH exome AF: 0.000178

GnomAD4 exome AF: 0.000211 AC: 306 AN: 1453406 Hom.: 0 Cov.: 32 AF XY: 0.000231 AC XY: 167 AN XY: 722572

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00647

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000197

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.000384

GnomAD4 genome AF: 0.000118 AC: 18 AN: 151932 Hom.: 0 Cov.: 33 AF XY: 0.0000944 AC XY: 7 AN XY: 74190

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00104 Hom.: 1

Bravo AF: 0.000136

ExAC AF: 0.000218 AC: 26

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Microcephaly 2, primary, autosomal recessive, with or without cortical malformations Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Seizure Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

New York Genome Center

Feb 07, 2020

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	20
Dann	Benign	0.93
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.62	T;T;T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	0.75	D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.59	N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.87	T;T;T
Polyphen		0.78	P;P;.
Vest4		0.67
MutPred		0.33		Loss of sheet (P = 0.003);Loss of sheet (P = 0.003);.;
MVP		0.77
MPC		0.63
ClinPred		0.27	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.57

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: rs761479779; hg19: chr19-36545994;