chr19-36101725-G-A

Variant names:

• chr19-36101725-G-A
• rs118175551
• NM_001083961.2:c.3033G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001083961.2(WDR62):​c.3033G>A​(p.Pro1011Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,551,608 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (48 hom.)
• Consequence: WDR62 NM_001083961.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.549
• Publications: 4 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=-0.76).
• BP6: Variant 19-36101725-G-A is Benign according to our data. Variant chr19-36101725-G-A is described in ClinVar as Benign. ClinVar VariationId is 160278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.549 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00214 (326/152262) while in subpopulation EAS AF = 0.0547 (283/5174). AF 95% confidence interval is 0.0495. There are 9 homozygotes in GnomAd4. There are 185 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR62	NM_001083961.2	MANE Select	c.3033G>A	p.Pro1011Pro	synonymous	Exon 25 of 32	NP_001077430.1	O43379-4
	WDR62	NM_001411145.1		c.3018G>A	p.Pro1006Pro	synonymous	Exon 25 of 32	NP_001398074.1	A0A7P0TAK3
	WDR62	NM_173636.5		c.3033G>A	p.Pro1011Pro	synonymous	Exon 25 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.3033G>A	p.Pro1011Pro	synonymous	Exon 25 of 32	ENSP00000384792.1	O43379-4
	WDR62	ENST00000587391.6	TSL:1	n.*2069G>A		non_coding_transcript_exon	Exon 25 of 30	ENSP00000465525.1	O43379-2
	WDR62	ENST00000587391.6	TSL:1	n.*2069G>A		3_prime_UTR	Exon 25 of 30	ENSP00000465525.1	O43379-2

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 325 AN: 152144 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0544

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00438 AC: 685 AN: 156492 AF XY: 0.00405

Gnomad AFR exome AF: 0.000230

Gnomad AMR exome AF: 0.000403

Gnomad ASJ exome AF: 0.000587

Gnomad EAS exome AF: 0.0554

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00316

GnomAD4 exome AF: 0.00150 AC: 2097 AN: 1399346 Hom.: 48 Cov.: 32 AF XY: 0.00145 AC XY: 1002 AN XY: 690216

African (AFR) AF: 0.000222 AC: 7 AN: 31600

American (AMR) AF: 0.000307 AC: 11 AN: 35776

Ashkenazi Jewish (ASJ) AF: 0.000596 AC: 15 AN: 25186

East Asian (EAS) AF: 0.0501 AC: 1793 AN: 35762

South Asian (SAS) AF: 0.000782 AC: 62 AN: 79254

European-Finnish (FIN) AF: 0.0000204 AC: 1 AN: 48948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5688

European-Non Finnish (NFE) AF: 0.0000408 AC: 44 AN: 1079106

Other (OTH) AF: 0.00283 AC: 164 AN: 58026

GnomAD4 genome AF: 0.00214 AC: 326 AN: 152262 Hom.: 9 Cov.: 33 AF XY: 0.00248 AC XY: 185 AN XY: 74448

African (AFR) AF: 0.000433 AC: 18 AN: 41570

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.0547 AC: 283 AN: 5174

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68002

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000328 Hom.: 0

Bravo AF: 0.00247

Asia WGS AF: 0.0180 AC: 63 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.2
DANN	Benign	0.79
PhyloP100		-0.55
Mutation Taster		=100/0	polymorphism

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: rs118175551; hg19: chr19-36592627; COSMIC: COSV54332769;