rs61734910

Variant names:

• chr19-36104837-T-G
• rs61734910
• NM_001083961.2:c.4381T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001083961.2(WDR62):​c.4381T>G​(p.Trp1461Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W1461C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.949
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774

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.4381T>G	p.Trp1461Gly	missense	Exon 32 of 32	NP_001077430.1	O43379-4
	WDR62	NM_001411145.1		c.4366T>G	p.Trp1456Gly	missense	Exon 32 of 32	NP_001398074.1	A0A7P0TAK3
	WDR62	NM_173636.5		c.4366T>G	p.Trp1456Gly	missense	Exon 32 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.4381T>G	p.Trp1461Gly	missense	Exon 32 of 32	ENSP00000384792.1	O43379-4
	WDR62	ENST00000587391.6	TSL:1	n.*4241T>G		non_coding_transcript_exon	Exon 30 of 30	ENSP00000465525.1	O43379-2
	WDR62	ENST00000587391.6	TSL:1	n.*4241T>G		3_prime_UTR	Exon 30 of 30	ENSP00000465525.1	O43379-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.013	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.096	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.95
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.55
Sift	Benign	0.29	T
Sift4G	Benign	0.65	T
Polyphen		1.0	D
Vest4		0.68
MutPred		0.66		Gain of disorder (P = 0.0085)
MVP		0.65
MPC		1.1
ClinPred		0.55	D
GERP RS		4.2
Varity_R		0.19
gMVP		0.31
Mutation Taster		=82/18	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: rs61734910; hg19: chr19-36595739;