19-36104534-A-T

Variant names:

• chr19-36104534-A-T
• rs1008328
• NM_001083961.2:c.4170A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001083961.2(WDR62):​c.4170A>T​(p.Leu1390Phe) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.126
• Publications: 36 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05147147).

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.4170A>T	p.Leu1390Phe	missense	Exon 31 of 32	NP_001077430.1	O43379-4
	WDR62	NM_001411145.1		c.4155A>T	p.Leu1385Phe	missense	Exon 31 of 32	NP_001398074.1	A0A7P0TAK3
	WDR62	NM_173636.5		c.4155A>T	p.Leu1385Phe	missense	Exon 31 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.4170A>T	p.Leu1390Phe	missense	Exon 31 of 32	ENSP00000384792.1	O43379-4
	WDR62	ENST00000587391.6	TSL:1	n.*4030A>T		non_coding_transcript_exon	Exon 29 of 30	ENSP00000465525.1	O43379-2
	WDR62	ENST00000587391.6	TSL:1	n.*4030A>T		3_prime_UTR	Exon 29 of 30	ENSP00000465525.1	O43379-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461574 Hom.: 0 Cov.: 76 AF XY: 0.00000138 AC XY: 1 AN XY: 727104

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.9
DANN	Benign	0.45
DEOGEN2	Benign	0.00089	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.083	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.13
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.056
Sift	Benign	0.31	T
Sift4G	Benign	0.56	T
Polyphen		0.0020	B
Vest4		0.029
MutPred		0.36		Loss of phosphorylation at S1388 (P = 0.1262)
MVP		0.29
MPC		0.24
ClinPred		0.50	D
GERP RS		2.0
Varity_R		0.047
gMVP		0.045
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1008328; hg19: chr19-36595436;