rs387907083

Variant names:

• chr19-36083222-G-A
• rs387907083
• NM_001083961.2:c.1531G>A
• WDR62 p.Asp511Asn

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PP3 PP5_Very_Strong

The NM_001083961.2(WDR62):​c.1531G>A​(p.Asp511Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000759 in 1,450,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004040078: Published functional studies demonstrate a damaging effect on microtubule localization (Lim et al., 2015)".

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.49
• Publications: 10 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, ClinGen, G2P, Illumina, Ambry Genetics
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004040078: Published functional studies demonstrate a damaging effect on microtubule localization (Lim et al., 2015)
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805
• PP5: Variant 19-36083222-G-A is Pathogenic according to our data. Variant chr19-36083222-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 31037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1531G>A	p.Asp511Asn	missense	Exon 11 of 32	NP_001077430.1	O43379-4
	WDR62	NM_001411145.1		c.1516G>A	p.Asp506Asn	missense	Exon 11 of 32	NP_001398074.1	A0A7P0TAK3
	WDR62	NM_173636.5		c.1531G>A	p.Asp511Asn	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.1531G>A	p.Asp511Asn	missense	Exon 11 of 32	ENSP00000384792.1	O43379-4
	WDR62	ENST00000587391.6	TSL:1	n.*221G>A		non_coding_transcript_exon	Exon 12 of 30	ENSP00000465525.1	O43379-2
	WDR62	ENST00000587391.6	TSL:1	n.*221G>A		3_prime_UTR	Exon 12 of 30	ENSP00000465525.1	O43379-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000876 AC: 2 AN: 228214 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000308

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000759 AC: 11 AN: 1450020 Hom.: 0 Cov.: 32 AF XY: 0.00000972 AC XY: 7 AN XY: 719992

African (AFR) AF: 0.00 AC: 0 AN: 33258

American (AMR) AF: 0.0000231 AC: 1 AN: 43238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25836

East Asian (EAS) AF: 0.00 AC: 0 AN: 39394

South Asian (SAS) AF: 0.0000237 AC: 2 AN: 84344

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5542

European-Non Finnish (NFE) AF: 0.00000723 AC: 8 AN: 1105938

Other (OTH) AF: 0.00 AC: 0 AN: 59904

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000244 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations (2)
1	-	-	Autosomal recessive primary microcephaly (1)
1	-	-	not provided (1)
1	-	-	Primary microcephaly type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		9.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.0090	D
Varity_R		0.56
gMVP		0.78
Mutation Taster		=16/84	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

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

dbSNP: rs387907083;

hg19: chr19-36574124;