19-36101683-C-T

Variant names:

• chr19-36101683-C-T
• rs77898819
• NM_001083961.2:c.2991C>T

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.2991C>T​(p.Ala997Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0088 in 1,550,910 control chromosomes in the GnomAD database, including 152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 33)
  • Exomes 𝑓: 0.0086 (140 hom.)
• Consequence: WDR62 NM_001083961.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.43
• 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=-0.68).
• BP6: Variant 19-36101683-C-T is Benign according to our data. Variant chr19-36101683-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.43 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0105 (1593/152252) while in subpopulation SAS AF = 0.0418 (201/4814). AF 95% confidence interval is 0.037. There are 12 homozygotes in GnomAd4. There are 833 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.2991C>T	p.Ala997Ala	synonymous	Exon 25 of 32	NP_001077430.1	O43379-4
	WDR62	NM_001411145.1		c.2976C>T	p.Ala992Ala	synonymous	Exon 25 of 32	NP_001398074.1	A0A7P0TAK3
	WDR62	NM_173636.5		c.2991C>T	p.Ala997Ala	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.2991C>T	p.Ala997Ala	synonymous	Exon 25 of 32	ENSP00000384792.1	O43379-4
	WDR62	ENST00000587391.6	TSL:1	n.*2027C>T		non_coding_transcript_exon	Exon 25 of 30	ENSP00000465525.1	O43379-2
	WDR62	ENST00000587391.6	TSL:1	n.*2027C>T		3_prime_UTR	Exon 25 of 30	ENSP00000465525.1	O43379-2

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1594 AN: 152134 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00739

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0413

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00657

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0120 AC: 1860 AN: 154824 AF XY: 0.0141

Gnomad AFR exome AF: 0.0146

Gnomad AMR exome AF: 0.00514

Gnomad ASJ exome AF: 0.0246

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00189

Gnomad NFE exome AF: 0.00740

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.00862 AC: 12054 AN: 1398658 Hom.: 140 Cov.: 32 AF XY: 0.00964 AC XY: 6650 AN XY: 689864

African (AFR) AF: 0.0186 AC: 587 AN: 31594

American (AMR) AF: 0.00546 AC: 195 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.0261 AC: 656 AN: 25178

East Asian (EAS) AF: 0.000112 AC: 4 AN: 35742

South Asian (SAS) AF: 0.0402 AC: 3187 AN: 79228

European-Finnish (FIN) AF: 0.00234 AC: 114 AN: 48682

Middle Eastern (MID) AF: 0.0267 AC: 151 AN: 5648

European-Non Finnish (NFE) AF: 0.00603 AC: 6510 AN: 1078886

Other (OTH) AF: 0.0112 AC: 650 AN: 57996

GnomAD4 genome AF: 0.0105 AC: 1593 AN: 152252 Hom.: 12 Cov.: 33 AF XY: 0.0112 AC XY: 833 AN XY: 74436

African (AFR) AF: 0.0163 AC: 677 AN: 41554

American (AMR) AF: 0.00738 AC: 113 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0418 AC: 201 AN: 4814

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10614

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00657 AC: 447 AN: 68006

Other (OTH) AF: 0.0142 AC: 30 AN: 2112

Alfa AF: 0.00765 Hom.: 1

Bravo AF: 0.0105

Asia WGS AF: 0.0140 AC: 48 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations (4)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	3.2
DANN	Benign	0.47
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs77898819; hg19: chr19-36592585;