19-36073526-G-T

Position:

• chr19-36073526-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_001083961.2(WDR62):​c.1228G>T​(p.Val410Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,613,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 2.50

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 Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01656875).
• BP6: Variant 19-36073526-G-T is Benign according to our data. Variant chr19-36073526-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167848.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000684 (104/151970) while in subpopulation AFR AF= 0.00239 (99/41394). AF 95% confidence interval is 0.00201. There are 0 homozygotes in gnomad4. There are 55 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WDR62	NM_001083961.2	c.1228G>T	p.Val410Leu	missense_variant	9/32	ENST00000401500.7	NP_001077430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WDR62	ENST00000401500.7	c.1228G>T	p.Val410Leu	missense_variant	9/32	1	NM_001083961.2	ENSP00000384792	P4

Frequencies

GnomAD3 genomes AF: 0.000678 AC: 103 AN: 151854 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.0000147

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000190 AC: 47 AN: 247914 Hom.: 0 AF XY: 0.000134 AC XY: 18 AN XY: 134568

Gnomad AFR exome AF: 0.00231

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000901

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000101 AC: 148 AN: 1461084 Hom.: 0 Cov.: 32 AF XY: 0.0000936 AC XY: 68 AN XY: 726824

Gnomad4 AFR exome AF: 0.00290

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000684 AC: 104 AN: 151970 Hom.: 0 Cov.: 32 AF XY: 0.000740 AC XY: 55 AN XY: 74296

Gnomad4 AFR AF: 0.00239

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000365 Hom.: 0

Bravo AF: 0.000771

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000222 AC: 27

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 20, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 19, 2016

- -

Microcephaly 2, primary, autosomal recessive, with or without cortical malformations Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 27, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	.;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.061
Sift	Benign	0.10	T;T
Sift4G	Uncertain	0.054	T;T
Polyphen		1.0	D;P
Vest4		0.17
MutPred		0.36		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.66
MPC		0.71
ClinPred		0.015	T
GERP RS		5.9
Varity_R		0.12
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

LitVar

Other links and lift over

dbSNP: rs139460397; hg19: chr19-36564428;