rs182467995

Variant names:

• chr19-36104763-T-G
• rs182467995
• NM_001083961.2:c.4312-5T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001083961.2(WDR62):​c.4312-5T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,613,760 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (7 hom.)
• Consequence: WDR62 NM_001083961.2 splice_region, intron
• Scores: Splicing: ADA: 0.1068
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:7
• Conservation: PhyloP100: 0.0100
• Publications: 2 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, Ambry Genetics, Illumina, G2P, ClinGen
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 19-36104763-T-G is Benign according to our data. Variant chr19-36104763-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 160302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00212 (323/152334) while in subpopulation NFE AF = 0.00391 (266/68018). AF 95% confidence interval is 0.00352. There are 2 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR62	NM_001083961.2	MANE Select	c.4312-5T>G		splice_region intron	N/A	NP_001077430.1
	WDR62	NM_001411145.1		c.4297-5T>G		splice_region intron	N/A	NP_001398074.1
	WDR62	NM_173636.5		c.4297-5T>G		splice_region intron	N/A	NP_775907.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR62	ENST00000401500.7	TSL:1 MANE Select	c.4312-5T>G		splice_region intron	N/A	ENSP00000384792.1
	WDR62	ENST00000587391.6	TSL:1	n.*4172-5T>G		splice_region intron	N/A	ENSP00000465525.1
	WDR62	ENST00000680403.1		c.*79T>G		3_prime_UTR	Exon 31 of 31	ENSP00000505677.1

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 325 AN: 152216 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00392

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00210 AC: 526 AN: 250210 AF XY: 0.00214

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00527

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000555

Gnomad NFE exome AF: 0.00340

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00338 AC: 4933 AN: 1461426 Hom.: 7 Cov.: 34 AF XY: 0.00330 AC XY: 2398 AN XY: 727030

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.000224 AC: 10 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00509 AC: 133 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00163 AC: 141 AN: 86256

European-Finnish (FIN) AF: 0.000529 AC: 28 AN: 52970

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00398 AC: 4424 AN: 1112006

Other (OTH) AF: 0.00306 AC: 185 AN: 60390

GnomAD4 genome AF: 0.00212 AC: 323 AN: 152334 Hom.: 2 Cov.: 32 AF XY: 0.00177 AC XY: 132 AN XY: 74486

African (AFR) AF: 0.000746 AC: 31 AN: 41576

American (AMR) AF: 0.000392 AC: 6 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00391 AC: 266 AN: 68018

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00289 Hom.: 1

Bravo AF: 0.00193

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00249

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	-	2	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.0
DANN	Benign	0.41
PhyloP100		0.010
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.11
dbscSNV1_RF	Benign	0.29
SpliceAI score (max)		0.10		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: rs182467995; hg19: chr19-36595665;