rs146274964

Variant names:

• chr19-36058855-G-A
• rs146274964
• NM_001083961.2:c.253G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001083961.2(WDR62):​c.253G>A​(p.Val85Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00272 in 1,614,138 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (8 hom.)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:5
• Conservation: PhyloP100: 1.27
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018250853).
• BP6: Variant 19-36058855-G-A is Benign according to our data. Variant chr19-36058855-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 328905.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0015 (229/152382) while in subpopulation NFE AF = 0.00267 (182/68040). AF 95% confidence interval is 0.00236. There are 0 homozygotes in GnomAd4. There are 103 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 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.253G>A	p.Val85Met	missense	Exon 2 of 32	NP_001077430.1	O43379-4
	WDR62	NM_001411145.1		c.253G>A	p.Val85Met	missense	Exon 2 of 32	NP_001398074.1	A0A7P0TAK3
	WDR62	NM_173636.5		c.253G>A	p.Val85Met	missense	Exon 2 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.253G>A	p.Val85Met	missense	Exon 2 of 32	ENSP00000384792.1	O43379-4
	WDR62	ENST00000587391.6	TSL:1	n.253G>A		non_coding_transcript_exon	Exon 2 of 30	ENSP00000465525.1	O43379-2
	WDR62	ENST00000679714.1		c.253G>A	p.Val85Met	missense	Exon 2 of 32	ENSP00000506627.1	A0A7P0TBE7

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 229 AN: 152264 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00267

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00121 AC: 304 AN: 251242 AF XY: 0.00113

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00226

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.00285 AC: 4166 AN: 1461756 Hom.: 8 Cov.: 32 AF XY: 0.00274 AC XY: 1991 AN XY: 727184

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86254

European-Finnish (FIN) AF: 0.00161 AC: 86 AN: 53404

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00355 AC: 3948 AN: 1111910

Other (OTH) AF: 0.00167 AC: 101 AN: 60386

GnomAD4 genome AF: 0.00150 AC: 229 AN: 152382 Hom.: 0 Cov.: 33 AF XY: 0.00138 AC XY: 103 AN XY: 74522

African (AFR) AF: 0.000721 AC: 30 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

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

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00267 AC: 182 AN: 68040

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00220 Hom.: 2

Bravo AF: 0.00134

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00118 AC: 143

EpiCase AF: 0.00229

EpiControl AF: 0.00219

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	3	-	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations (3)
-	2	-	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	WDR62-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0092	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.64	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.99	D
Vest4		0.58
MVP		0.64
MPC		0.80
ClinPred		0.046	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.48
Mutation Taster		=94/6	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: rs146274964; hg19: chr19-36549757; COSMIC: COSV99035367; COSMIC: COSV99035367;