rs61494900

Variant names:

• chr19-36092749-G-A
• rs61494900
• NM_001083961.2:c.2271G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001083961.2(WDR62):​c.2271G>A​(p.Leu757Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,952 control chromosomes in the GnomAD database, including 10,458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1794 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8664 hom.)
• Consequence: WDR62 NM_001083961.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.716
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 19-36092749-G-A is Benign according to our data. Variant chr19-36092749-G-A is described in ClinVar as Benign. ClinVar VariationId is 160263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.716 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.225 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.2271G>A	p.Leu757Leu	synonymous	Exon 19 of 32	NP_001077430.1	O43379-4
	WDR62	NM_001411145.1		c.2256G>A	p.Leu752Leu	synonymous	Exon 19 of 32	NP_001398074.1	A0A7P0TAK3
	WDR62	NM_173636.5		c.2271G>A	p.Leu757Leu	synonymous	Exon 19 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.2271G>A	p.Leu757Leu	synonymous	Exon 19 of 32	ENSP00000384792.1	O43379-4
	WDR62	ENST00000587391.6	TSL:1	n.*961G>A		non_coding_transcript_exon	Exon 20 of 30	ENSP00000465525.1	O43379-2
	WDR62	ENST00000587391.6	TSL:1	n.*961G>A		3_prime_UTR	Exon 20 of 30	ENSP00000465525.1	O43379-2

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20997 AN: 152024 Hom.: 1794 Cov.: 32

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0893

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.158

GnomAD2 exomes AF: 0.104 AC: 26257 AN: 251408 AF XY: 0.105

Gnomad AFR exome AF: 0.234

Gnomad AMR exome AF: 0.0746

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.104 AC: 152177 AN: 1461810 Hom.: 8664 Cov.: 33 AF XY: 0.104 AC XY: 75935 AN XY: 727204

African (AFR) AF: 0.233 AC: 7799 AN: 33476

American (AMR) AF: 0.0783 AC: 3503 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 3203 AN: 26130

East Asian (EAS) AF: 0.000428 AC: 17 AN: 39698

South Asian (SAS) AF: 0.0917 AC: 7908 AN: 86256

European-Finnish (FIN) AF: 0.109 AC: 5828 AN: 53402

Middle Eastern (MID) AF: 0.194 AC: 1117 AN: 5768

European-Non Finnish (NFE) AF: 0.104 AC: 116006 AN: 1111964

Other (OTH) AF: 0.113 AC: 6796 AN: 60392

GnomAD4 genome AF: 0.138 AC: 21012 AN: 152142 Hom.: 1794 Cov.: 32 AF XY: 0.137 AC XY: 10164 AN XY: 74392

African (AFR) AF: 0.229 AC: 9497 AN: 41488

American (AMR) AF: 0.108 AC: 1652 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 459 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.0894 AC: 431 AN: 4822

European-Finnish (FIN) AF: 0.116 AC: 1224 AN: 10590

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7233 AN: 67992

Other (OTH) AF: 0.157 AC: 331 AN: 2114

Alfa AF: 0.128 Hom.: 609

Bravo AF: 0.143

Asia WGS AF: 0.0520 AC: 183 AN: 3478

EpiCase AF: 0.123

EpiControl AF: 0.130

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	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	-0.47
CADD	Benign	10
DANN	Benign	0.67
PhyloP100		0.72
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs61494900; hg19: chr19-36583651;