NM_001083961.2:c.2972A>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_001083961.2(WDR62):c.2972A>T(p.Asp991Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000935 in 1,550,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D991E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000095 ( 0 hom. )

Consequence

WDR62
NM_001083961.2 missense, splice_region

Scores

Splicing: ADA: 0.01497

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 1.87

Publications

1 publications found

Variant links:

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

WDR62 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14906567).

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000951 (133/1398162) while in subpopulation MID AF = 0.00195 (11/5632). AF 95% confidence interval is 0.0011. There are 0 homozygotes in GnomAdExome4. There are 73 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WDR62	NM_001083961.2	MANE Select	c.2972A>T	p.Asp991Val	missense splice_region	Exon 25 of 32	NP_001077430.1
WDR62	NM_001411145.1		c.2957A>T	p.Asp986Val	missense splice_region	Exon 25 of 32	NP_001398074.1
WDR62	NM_173636.5		c.2972A>T	p.Asp991Val	missense splice_region	Exon 25 of 32	NP_775907.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
WDR62	ENST00000401500.7	TSL:1 MANE Select	c.2972A>T	p.Asp991Val	missense splice_region	Exon 25 of 32	ENSP00000384792.1
WDR62	ENST00000587391.6	TSL:1	n.*2008A>T		non_coding_transcript_exon	Exon 25 of 30	ENSP00000465525.1
WDR62	ENST00000587391.6	TSL:1	n.*2008A>T		3_prime_UTR	Exon 25 of 30	ENSP00000465525.1

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151906

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000104

AC:

AN:

154200

AF XY:

0.000110

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000510

Gnomad OTH exome

AF:

0.000911

GnomAD4 exome

AF:

0.0000951

AC:

133

AN:

1398162

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

689626

show subpopulations

African (AFR)

AF:

0.000412

AC:

AN:

31554

American (AMR)

AF:

0.000112

AC:

AN:

35702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25174

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.000101

AC:

AN:

79220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48660

Middle Eastern (MID)

AF:

0.00195

AC:

AN:

5632

European-Non Finnish (NFE)

AF:

0.0000751

AC:

AN:

1078496

Other (OTH)

AF:

0.000276

AC:

AN:

57986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152022

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41462

American (AMR)

AF:

0.000131

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5140

South Asian (SAS)

AF:

0.000415

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

67976

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000158

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000562

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Microcephaly 2, primary, autosomal recessive, with or without cortical malformations (3)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.13

Eigen

Benign

0.12

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.81

M_CAP

Benign

0.067

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.92

MutationAssessor

Benign

2.0

PhyloP100

1.9

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.18

Sift

Uncertain

0.0040

Sift4G

Benign

0.067

Polyphen

0.78

Vest4

0.43

MVP

0.52

MPC

0.70

ClinPred

0.072

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.19

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.015

dbscSNV1_RF

Benign

0.16

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over