NM_001083961.2:c.1315T>G

Variant names:

• chr19-36081514-T-G
• rs75230537
• NM_001083961.2:c.1315T>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001083961.2(WDR62):​c.1315T>G​(p.Phe439Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,614,178 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (32 hom.)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.895
• Publications: 7 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, Ambry Genetics, Illumina, G2P, ClinGen
• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 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, 4 uncertain in NM_001083961.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.012575388).
• BP6: Variant 19-36081514-T-G is Benign according to our data. Variant chr19-36081514-T-G is described in ClinVar as Benign. ClinVar VariationId is 160247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0106 (1609/152288) while in subpopulation AFR AF = 0.0372 (1546/41548). AF 95% confidence interval is 0.0357. There are 28 homozygotes in GnomAd4. There are 779 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR62	NM_001083961.2	MANE Select	c.1315T>G	p.Phe439Val	missense	Exon 10 of 32	NP_001077430.1
	WDR62	NM_001411145.1		c.1300T>G	p.Phe434Val	missense	Exon 10 of 32	NP_001398074.1
	WDR62	NM_173636.5		c.1315T>G	p.Phe439Val	missense	Exon 10 of 32	NP_775907.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR62	ENST00000401500.7	TSL:1 MANE Select	c.1315T>G	p.Phe439Val	missense	Exon 10 of 32	ENSP00000384792.1
	WDR62	ENST00000587391.6	TSL:1	n.1315T>G		non_coding_transcript_exon	Exon 10 of 30	ENSP00000465525.1
	WDR62	ENST00000679714.1		c.1309T>G	p.Phe437Val	missense	Exon 10 of 32	ENSP00000506627.1

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1602 AN: 152170 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0372

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00252 AC: 635 AN: 251490 AF XY: 0.00173

Gnomad AFR exome AF: 0.0359

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00101 AC: 1482 AN: 1461890 Hom.: 32 Cov.: 34 AF XY: 0.000875 AC XY: 636 AN XY: 727246

African (AFR) AF: 0.0366 AC: 1225 AN: 33476

American (AMR) AF: 0.00163 AC: 73 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1112012

Other (OTH) AF: 0.00204 AC: 123 AN: 60396

GnomAD4 genome AF: 0.0106 AC: 1609 AN: 152288 Hom.: 28 Cov.: 32 AF XY: 0.0105 AC XY: 779 AN XY: 74478

African (AFR) AF: 0.0372 AC: 1546 AN: 41548

American (AMR) AF: 0.00301 AC: 46 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68018

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00140 Hom.: 16

Bravo AF: 0.0116

ESP6500AA AF: 0.0354 AC: 156

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00315 AC: 383

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.037
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.080	N
PhyloP100		0.90
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.54	N
REVEL	Benign	0.10
Sift	Benign	0.48	T
Sift4G	Benign	0.43	T
Polyphen		0.83	P
Vest4		0.39
MVP		0.59
MPC		0.49
ClinPred		0.028	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.090
gMVP		0.63
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs75230537; hg19: chr19-36572416;