rs587784545

Variant names:

• chr19-36086725-A-T
• rs587784545
• NM_001083961.2:c.1681A>T

Your query was ambiguous. Multiple possible variants found:

• chr19-36086725-A-T
• chr19-36086725-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_001083961.2(WDR62):​c.1681A>T​(p.Ile561Phe) variant causes a missense change involving the alteration of a 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.51
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

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.1681A>T	p.Ile561Phe	missense	Exon 13 of 32	NP_001077430.1	O43379-4
	WDR62	NM_001411145.1		c.1666A>T	p.Ile556Phe	missense	Exon 13 of 32	NP_001398074.1	A0A7P0TAK3
	WDR62	NM_173636.5		c.1681A>T	p.Ile561Phe	missense	Exon 13 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.1681A>T	p.Ile561Phe	missense	Exon 13 of 32	ENSP00000384792.1	O43379-4
	WDR62	ENST00000587391.6	TSL:1	n.*371A>T		non_coding_transcript_exon	Exon 14 of 30	ENSP00000465525.1	O43379-2
	WDR62	ENST00000587391.6	TSL:1	n.*371A>T		3_prime_UTR	Exon 14 of 30	ENSP00000465525.1	O43379-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.61		Gain of catalytic residue at I561 (P = 0.0568)
MVP		0.81
MPC		1.0
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.63
gMVP		0.73
Mutation Taster		=30/70	disease causing

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: rs587784545; hg19: chr19-36577627;