19-36073536-GCCC-GCC

Variant names:

• chr19-36073536-GC-G
• rs373693641
• NM_001083961.2:c.1233+15delC

Variant summary

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

The ENST00000401500.7(WDR62):​c.1233+6delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00717 in 1,270,004 control chromosomes in the GnomAD database, including 22 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0057 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0074 (17 hom.)
• Consequence: WDR62 ENST00000401500.7 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.491
• 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), Laboratory for Molecular Medicine, ClinGen, G2P, Illumina, Ambry Genetics
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP6: Variant 19-36073536-GC-G is Benign according to our data. Variant chr19-36073536-GC-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212597.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00567 (831/146662) while in subpopulation AFR AF = 0.0153 (608/39666). AF 95% confidence interval is 0.0143. There are 5 homozygotes in GnomAd4. There are 377 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000401500.7. 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.1233+15delC		intron	N/A	NP_001077430.1	O43379-4
	WDR62	NM_001411145.1		c.1218+15delC		intron	N/A	NP_001398074.1	A0A7P0TAK3
	WDR62	NM_173636.5		c.1233+15delC		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.1233+6delC		splice_region intron	N/A	ENSP00000384792.1	O43379-4
	WDR62	ENST00000587391.6	TSL:1	n.1233+6delC		splice_region intron	N/A	ENSP00000465525.1	O43379-2
	WDR62	ENST00000679714.1		c.1227+12delC		intron	N/A	ENSP00000506627.1	A0A7P0TBE7

Frequencies

GnomAD3 genomes AF: 0.00564 AC: 826 AN: 146582 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00273

Gnomad ASJ AF: 0.000293

Gnomad EAS AF: 0.00159

Gnomad SAS AF: 0.00416

Gnomad FIN AF: 0.000101

Gnomad MID AF: 0.00327

Gnomad NFE AF: 0.00223

Gnomad OTH AF: 0.00298

GnomAD4 exome AF: 0.00736 AC: 8273 AN: 1123342 Hom.: 17 Cov.: 28 AF XY: 0.00739 AC XY: 4175 AN XY: 565016

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0236 AC: 631 AN: 26792

American (AMR) AF: 0.00668 AC: 262 AN: 39218

Ashkenazi Jewish (ASJ) AF: 0.00290 AC: 60 AN: 20724

East Asian (EAS) AF: 0.00608 AC: 188 AN: 30928

South Asian (SAS) AF: 0.00815 AC: 637 AN: 78126

European-Finnish (FIN) AF: 0.0101 AC: 424 AN: 41918

Middle Eastern (MID) AF: 0.00821 AC: 39 AN: 4748

European-Non Finnish (NFE) AF: 0.00675 AC: 5629 AN: 834298

Other (OTH) AF: 0.00865 AC: 403 AN: 46590

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00567 AC: 831 AN: 146662 Hom.: 5 Cov.: 31 AF XY: 0.00528 AC XY: 377 AN XY: 71348

African (AFR) AF: 0.0153 AC: 608 AN: 39666

American (AMR) AF: 0.00266 AC: 39 AN: 14662

Ashkenazi Jewish (ASJ) AF: 0.000293 AC: 1 AN: 3410

East Asian (EAS) AF: 0.00159 AC: 8 AN: 5020

South Asian (SAS) AF: 0.00416 AC: 19 AN: 4562

European-Finnish (FIN) AF: 0.000101 AC: 1 AN: 9902

Middle Eastern (MID) AF: 0.00355 AC: 1 AN: 282

European-Non Finnish (NFE) AF: 0.00223 AC: 148 AN: 66222

Other (OTH) AF: 0.00295 AC: 6 AN: 2036

Alfa AF: 0.00558 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	not provided (1)
-	1	-	Primary Microcephaly 2 With or Without Cortical Malformations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs373693641;

hg19: chr19-36564438;

COSMIC: COSV54332047;

COSMIC: COSV54332047;