19-36058788-C-T

Variant names:

• chr19-36058788-C-T
• rs11538454
• NM_001083961.2:c.186C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001083961.2(WDR62):​c.186C>T​(p.Leu62Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,612,986 control chromosomes in the GnomAD database, including 30,791 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L62L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.15 (2186 hom., cov: 33)
  • Exomes 𝑓: 0.19 (28605 hom.)
• Consequence: WDR62 NM_001083961.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.79
• Publications: 14 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 19-36058788-C-T is Benign according to our data. Variant chr19-36058788-C-T is described in ClinVar as Benign. ClinVar VariationId is 137909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.79 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.204 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR62	NM_001083961.2	MANE Select	c.186C>T	p.Leu62Leu	synonymous	Exon 2 of 32	NP_001077430.1
	WDR62	NM_001411145.1		c.186C>T	p.Leu62Leu	synonymous	Exon 2 of 32	NP_001398074.1
	WDR62	NM_173636.5		c.186C>T	p.Leu62Leu	synonymous	Exon 2 of 32	NP_775907.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR62	ENST00000401500.7	TSL:1 MANE Select	c.186C>T	p.Leu62Leu	synonymous	Exon 2 of 32	ENSP00000384792.1
	WDR62	ENST00000587391.6	TSL:1	n.186C>T		non_coding_transcript_exon	Exon 2 of 30	ENSP00000465525.1
	WDR62	ENST00000679714.1		c.186C>T	p.Leu62Leu	synonymous	Exon 2 of 32	ENSP00000506627.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22924 AN: 152118 Hom.: 2185 Cov.: 33

Gnomad AFR AF: 0.0384

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.161

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.156

GnomAD2 exomes AF: 0.179 AC: 44920 AN: 250836 AF XY: 0.184

Gnomad AFR exome AF: 0.0352

Gnomad AMR exome AF: 0.150

Gnomad ASJ exome AF: 0.223

Gnomad EAS exome AF: 0.194

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.204

Gnomad OTH exome AF: 0.198

GnomAD4 exome AF: 0.195 AC: 284574 AN: 1460750 Hom.: 28605 Cov.: 33 AF XY: 0.195 AC XY: 141879 AN XY: 726702

African (AFR) AF: 0.0321 AC: 1074 AN: 33474

American (AMR) AF: 0.150 AC: 6686 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 5986 AN: 26118

East Asian (EAS) AF: 0.178 AC: 7059 AN: 39686

South Asian (SAS) AF: 0.181 AC: 15585 AN: 86230

European-Finnish (FIN) AF: 0.171 AC: 9145 AN: 53378

Middle Eastern (MID) AF: 0.231 AC: 1326 AN: 5750

European-Non Finnish (NFE) AF: 0.203 AC: 226097 AN: 1111078

Other (OTH) AF: 0.193 AC: 11616 AN: 60336

GnomAD4 genome AF: 0.151 AC: 22922 AN: 152236 Hom.: 2186 Cov.: 33 AF XY: 0.150 AC XY: 11140 AN XY: 74426

African (AFR) AF: 0.0383 AC: 1593 AN: 41574

American (AMR) AF: 0.157 AC: 2402 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 796 AN: 3470

East Asian (EAS) AF: 0.183 AC: 946 AN: 5168

South Asian (SAS) AF: 0.169 AC: 815 AN: 4820

European-Finnish (FIN) AF: 0.161 AC: 1705 AN: 10594

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14068 AN: 67998

Other (OTH) AF: 0.157 AC: 332 AN: 2116

Alfa AF: 0.174 Hom.: 1649

Bravo AF: 0.145

Asia WGS AF: 0.162 AC: 564 AN: 3478

EpiCase AF: 0.205

EpiControl AF: 0.212

ClinVar

ClinVar submissions as Germline

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)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	2.8
DANN	Benign	0.81
PhyloP100		-3.8
Mutation Taster		=92/8	polymorphism (auto)

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: rs11538454; hg19: chr19-36549690; COSMIC: COSV53077850; COSMIC: COSV53077850;