19-36083200-C-G

Variant names:

• chr19-36083200-C-G
• NM_001083961.2:c.1509C>G
• WDR62 p.Asp503Glu

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001083961.2(WDR62):​c.1509C>G​(p.Asp503Glu) 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 benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D503G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.457
• 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 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001083961.2
• PM2: Very rare variant in population databases, with high coverage

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.1509C>G	p.Asp503Glu	missense	Exon 11 of 32	NP_001077430.1	O43379-4
	WDR62	NM_001411145.1		c.1494C>G	p.Asp498Glu	missense	Exon 11 of 32	NP_001398074.1	A0A7P0TAK3
	WDR62	NM_173636.5		c.1509C>G	p.Asp503Glu	missense	Exon 11 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.1509C>G	p.Asp503Glu	missense	Exon 11 of 32	ENSP00000384792.1	O43379-4
	WDR62	ENST00000587391.6	TSL:1	n.*199C>G		non_coding_transcript_exon	Exon 12 of 30	ENSP00000465525.1	O43379-2
	WDR62	ENST00000587391.6	TSL:1	n.*199C>G		3_prime_UTR	Exon 12 of 30	ENSP00000465525.1	O43379-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	0.0066	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	11
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-0.46
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.22
Sift	Benign	0.085	T
Sift4G	Benign	0.072	T
Varity_R		0.29
gMVP		0.66
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.26		Position offset: 41

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr19-36574102;