rs797046108

Variant names:

• chr19-36058881-TA-T
• rs797046108
• NM_001083961.2:c.269+12delA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001083961.2(WDR62):​c.269+12delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00782 in 1,610,434 control chromosomes in the GnomAD database, including 140 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0056 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (130 hom.)
• Consequence: WDR62 NM_001083961.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.0610
• Publications: 0 publications found

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]

WDR62 Gene-Disease associations (from GenCC):

• microcephaly 2, primary, autosomal recessive, with or without cortical malformations

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics, Laboratory for Molecular Medicine, G2P, ClinGen
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 19-36058881-TA-T is Benign according to our data. Variant chr19-36058881-TA-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212602.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0056 (854/152380) while in subpopulation SAS AF = 0.0418 (202/4834). AF 95% confidence interval is 0.0371. There are 10 homozygotes in GnomAd4. There are 464 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083961.2. 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
	WDR62	NM_001083961.2	MANE Select	c.269+12delA		intron	N/A	NP_001077430.1	O43379-4
	WDR62	NM_001411145.1		c.269+12delA		intron	N/A	NP_001398074.1	A0A7P0TAK3
	WDR62	NM_173636.5		c.269+12delA		intron	N/A	NP_775907.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR62	ENST00000401500.7	TSL:1 MANE Select	c.269+11delA		intron	N/A	ENSP00000384792.1	O43379-4
	WDR62	ENST00000587391.6	TSL:1	n.269+11delA		intron	N/A	ENSP00000465525.1	O43379-2
	WDR62	ENST00000679714.1		c.269+11delA		intron	N/A	ENSP00000506627.1	A0A7P0TBE7

Frequencies

GnomAD3 genomes AF: 0.00561 AC: 854 AN: 152262 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0413

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00647

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00963 AC: 2409 AN: 250244 AF XY: 0.0116

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.00310

Gnomad ASJ exome AF: 0.0234

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00692

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.00805 AC: 11742 AN: 1458054 Hom.: 130 Cov.: 30 AF XY: 0.00920 AC XY: 6671 AN XY: 725488

African (AFR) AF: 0.00117 AC: 39 AN: 33414

American (AMR) AF: 0.00327 AC: 146 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.0247 AC: 644 AN: 26104

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39654

South Asian (SAS) AF: 0.0400 AC: 3448 AN: 86136

European-Finnish (FIN) AF: 0.00238 AC: 127 AN: 53394

Middle Eastern (MID) AF: 0.0208 AC: 120 AN: 5758

European-Non Finnish (NFE) AF: 0.00600 AC: 6647 AN: 1108650

Other (OTH) AF: 0.00937 AC: 565 AN: 60284

GnomAD4 genome AF: 0.00560 AC: 854 AN: 152380 Hom.: 10 Cov.: 32 AF XY: 0.00623 AC XY: 464 AN XY: 74518

African (AFR) AF: 0.000673 AC: 28 AN: 41592

American (AMR) AF: 0.00307 AC: 47 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.0418 AC: 202 AN: 4834

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10628

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00647 AC: 440 AN: 68036

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.00805 Hom.: 1

Bravo AF: 0.00472

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	1	-	Primary Microcephaly 2 With or Without Cortical Malformations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.061
Mutation Taster		=99/1	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: rs797046108; hg19: chr19-36549783;