19-36101667-C-T

Variant names:

• chr19-36101667-C-T
• rs74518295
• NM_001083961.2:c.2975C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001083961.2(WDR62):​c.2975C>T​(p.Ser992Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,550,406 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S992S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0088 (17 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (16 hom.)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0800
• 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), 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031680763).
• BP6: Variant 19-36101667-C-T is Benign according to our data. Variant chr19-36101667-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 160276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00876 (1334/152284) while in subpopulation AFR AF = 0.0297 (1236/41558). AF 95% confidence interval is 0.0284. There are 17 homozygotes in GnomAd4. There are 626 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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.2975C>T	p.Ser992Leu	missense	Exon 25 of 32	NP_001077430.1
	WDR62	NM_001411145.1		c.2960C>T	p.Ser987Leu	missense	Exon 25 of 32	NP_001398074.1
	WDR62	NM_173636.5		c.2975C>T	p.Ser992Leu	missense	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.2975C>T	p.Ser992Leu	missense	Exon 25 of 32	ENSP00000384792.1
	WDR62	ENST00000587391.6	TSL:1	n.*2011C>T		non_coding_transcript_exon	Exon 25 of 30	ENSP00000465525.1
	WDR62	ENST00000587391.6	TSL:1	n.*2011C>T		3_prime_UTR	Exon 25 of 30	ENSP00000465525.1

Frequencies

GnomAD3 genomes AF: 0.00877 AC: 1334 AN: 152168 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.0298

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00861

GnomAD2 exomes AF: 0.00233 AC: 359 AN: 154156 AF XY: 0.00169

Gnomad AFR exome AF: 0.0309

Gnomad AMR exome AF: 0.00146

Gnomad ASJ exome AF: 0.000472

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000652

Gnomad NFE exome AF: 0.000764

Gnomad OTH exome AF: 0.00319

GnomAD4 exome AF: 0.00118 AC: 1652 AN: 1398122 Hom.: 16 Cov.: 32 AF XY: 0.00105 AC XY: 722 AN XY: 689614

African (AFR) AF: 0.0311 AC: 982 AN: 31572

American (AMR) AF: 0.00232 AC: 83 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.000397 AC: 10 AN: 25174

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79218

European-Finnish (FIN) AF: 0.0000205 AC: 1 AN: 48664

Middle Eastern (MID) AF: 0.00373 AC: 21 AN: 5630

European-Non Finnish (NFE) AF: 0.000382 AC: 412 AN: 1078452

Other (OTH) AF: 0.00245 AC: 142 AN: 57976

GnomAD4 genome AF: 0.00876 AC: 1334 AN: 152284 Hom.: 17 Cov.: 33 AF XY: 0.00841 AC XY: 626 AN XY: 74460

African (AFR) AF: 0.0297 AC: 1236 AN: 41558

American (AMR) AF: 0.00373 AC: 57 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68032

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00308 Hom.: 11

Bravo AF: 0.0105

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0239 AC: 93

ESP6500EA AF: 0.000682 AC: 5

ExAC AF: 0.00198 AC: 108

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations (3)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	WDR62-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.080
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.044
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.074	T
Polyphen		0.0090	B
Vest4		0.099
MVP		0.43
MPC		0.21
ClinPred		0.0083	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.099
gMVP		0.085
Mutation Taster		=98/2	polymorphism

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: rs74518295; hg19: chr19-36592569;