NM_001083961.2:c.3812C>T

Variant names:

• chr19-36103640-C-T
• rs111294536
• NM_001083961.2:c.3812C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001083961.2(WDR62):​c.3812C>T​(p.Ala1271Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 1,609,386 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1271T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (23 hom.)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.401
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037599802).
• BP6: Variant 19-36103640-C-T is Benign according to our data. Variant chr19-36103640-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00295 (445/151088) while in subpopulation NFE AF = 0.00553 (374/67604). AF 95% confidence interval is 0.00507. There are 0 homozygotes in GnomAd4. There are 192 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 23 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.3812C>T	p.Ala1271Val	missense	Exon 30 of 32	NP_001077430.1
	WDR62	NM_001411145.1		c.3797C>T	p.Ala1266Val	missense	Exon 30 of 32	NP_001398074.1
	WDR62	NM_173636.5		c.3797C>T	p.Ala1266Val	missense	Exon 30 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.3812C>T	p.Ala1271Val	missense	Exon 30 of 32	ENSP00000384792.1
	WDR62	ENST00000587391.6	TSL:1	n.*3672C>T		non_coding_transcript_exon	Exon 28 of 30	ENSP00000465525.1
	WDR62	ENST00000587391.6	TSL:1	n.*3672C>T		3_prime_UTR	Exon 28 of 30	ENSP00000465525.1

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 445 AN: 150968 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000757

Gnomad AMI AF: 0.00222

Gnomad AMR AF: 0.000329

Gnomad ASJ AF: 0.00232

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.00152

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00553

Gnomad OTH AF: 0.00193

GnomAD2 exomes AF: 0.00283 AC: 704 AN: 248548 AF XY: 0.00276

Gnomad AFR exome AF: 0.000618

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00201

Gnomad NFE exome AF: 0.00510

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00450 AC: 6556 AN: 1458298 Hom.: 23 Cov.: 34 AF XY: 0.00441 AC XY: 3201 AN XY: 725624

African (AFR) AF: 0.000657 AC: 22 AN: 33478

American (AMR) AF: 0.000626 AC: 28 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00341 AC: 89 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.000591 AC: 51 AN: 86258

European-Finnish (FIN) AF: 0.00182 AC: 91 AN: 49870

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00544 AC: 6049 AN: 1111992

Other (OTH) AF: 0.00356 AC: 215 AN: 60376

GnomAD4 genome AF: 0.00295 AC: 445 AN: 151088 Hom.: 0 Cov.: 33 AF XY: 0.00260 AC XY: 192 AN XY: 73860

African (AFR) AF: 0.000754 AC: 31 AN: 41094

American (AMR) AF: 0.000328 AC: 5 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00232 AC: 8 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5088

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4770

European-Finnish (FIN) AF: 0.00152 AC: 16 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00553 AC: 374 AN: 67604

Other (OTH) AF: 0.00191 AC: 4 AN: 2094

Alfa AF: 0.00419 Hom.: 1

Bravo AF: 0.00250

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00651 AC: 56

ExAC AF: 0.00294 AC: 357

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00453

EpiControl AF: 0.00480

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 13, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 06, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

WDR62: BP4, BS2

not specified Benign:3

Oct 19, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 23, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Microcephaly 2, primary, autosomal recessive, with or without cortical malformations Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Inborn genetic diseases Benign:1

Sep 13, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.1
DANN	Benign	0.22
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.40
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.025
Sift	Benign	0.75	T
Sift4G	Benign	0.25	T
Polyphen		0.31	B
Vest4		0.049
MVP		0.41
MPC		0.22
ClinPred		0.0023	T
GERP RS		-2.7
Varity_R		0.035
gMVP		0.12
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs111294536; hg19: chr19-36594542; COSMIC: COSV54334065;