rs45470992

Variant names:

• chr19-36103467-C-T
• rs45470992
• NM_001083961.2:c.3639C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001083961.2(WDR62):​c.3639C>T​(p.Ser1213Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 1,614,136 control chromosomes in the GnomAD database, including 1,424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (126 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1298 hom.)
• Consequence: WDR62 NM_001083961.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.687
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 19-36103467-C-T is Benign according to our data. Variant chr19-36103467-C-T is described in ClinVar as Benign. ClinVar VariationId is 160294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

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.3639C>T	p.Ser1213Ser	synonymous	Exon 30 of 32	NP_001077430.1	O43379-4
	WDR62	NM_001411145.1		c.3624C>T	p.Ser1208Ser	synonymous	Exon 30 of 32	NP_001398074.1	A0A7P0TAK3
	WDR62	NM_173636.5		c.3624C>T	p.Ser1208Ser	synonymous	Exon 30 of 32	NP_775907.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR62	ENST00000401500.7	TSL:1 MANE Select	c.3639C>T	p.Ser1213Ser	synonymous	Exon 30 of 32	ENSP00000384792.1	O43379-4
	WDR62	ENST00000587391.6	TSL:1	n.*3499C>T		non_coding_transcript_exon	Exon 28 of 30	ENSP00000465525.1	O43379-2
	WDR62	ENST00000587391.6	TSL:1	n.*3499C>T		3_prime_UTR	Exon 28 of 30	ENSP00000465525.1	O43379-2

Frequencies

GnomAD3 genomes AF: 0.0326 AC: 4967 AN: 152154 Hom.: 123 Cov.: 33

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0269

Gnomad ASJ AF: 0.0634

Gnomad EAS AF: 0.111

Gnomad SAS AF: 0.0640

Gnomad FIN AF: 0.0308

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0357

Gnomad OTH AF: 0.0387

GnomAD2 exomes AF: 0.0435 AC: 10947 AN: 251382 AF XY: 0.0450

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.0633

Gnomad EAS exome AF: 0.121

Gnomad FIN exome AF: 0.0328

Gnomad NFE exome AF: 0.0370

Gnomad OTH exome AF: 0.0414

GnomAD4 exome AF: 0.0377 AC: 55110 AN: 1461864 Hom.: 1298 Cov.: 34 AF XY: 0.0387 AC XY: 28116 AN XY: 727230

African (AFR) AF: 0.0140 AC: 469 AN: 33480

American (AMR) AF: 0.0203 AC: 908 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0666 AC: 1740 AN: 26136

East Asian (EAS) AF: 0.104 AC: 4124 AN: 39700

South Asian (SAS) AF: 0.0612 AC: 5280 AN: 86258

European-Finnish (FIN) AF: 0.0328 AC: 1753 AN: 53392

Middle Eastern (MID) AF: 0.0392 AC: 226 AN: 5768

European-Non Finnish (NFE) AF: 0.0341 AC: 37879 AN: 1112010

Other (OTH) AF: 0.0452 AC: 2731 AN: 60396

GnomAD4 genome AF: 0.0327 AC: 4974 AN: 152272 Hom.: 126 Cov.: 33 AF XY: 0.0328 AC XY: 2445 AN XY: 74444

African (AFR) AF: 0.0143 AC: 594 AN: 41562

American (AMR) AF: 0.0268 AC: 411 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0634 AC: 220 AN: 3470

East Asian (EAS) AF: 0.111 AC: 573 AN: 5172

South Asian (SAS) AF: 0.0637 AC: 307 AN: 4822

European-Finnish (FIN) AF: 0.0308 AC: 327 AN: 10620

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0358 AC: 2431 AN: 67998

Other (OTH) AF: 0.0430 AC: 91 AN: 2114

Alfa AF: 0.0356 Hom.: 59

Bravo AF: 0.0309

Asia WGS AF: 0.132 AC: 458 AN: 3478

EpiCase AF: 0.0378

EpiControl AF: 0.0348

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.7
DANN	Benign	0.57
PhyloP100		-0.69
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs45470992; hg19: chr19-36594369; COSMIC: COSV54336952;