19-36103774-C-G

Variant names:

• chr19-36103774-C-G
• rs35811023
• NM_001083961.2:c.3946C>G

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.3946C>G​(p.Gln1316Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00561 in 1,610,452 control chromosomes in the GnomAD database, including 26 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Q1316Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (24 hom.)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.453
• 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), Illumina, Ambry Genetics, Laboratory for Molecular Medicine, 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=0.0041314065).
• BP6: Variant 19-36103774-C-G is Benign according to our data. Variant chr19-36103774-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93539.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 = 0.00405 (617/152184) while in subpopulation NFE AF = 0.00688 (468/67984). AF 95% confidence interval is 0.00637. There are 2 homozygotes in GnomAd4. There are 252 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR62	NM_001083961.2	MANE Select	c.3946C>G	p.Gln1316Glu	missense	Exon 30 of 32	NP_001077430.1	O43379-4
	WDR62	NM_001411145.1		c.3931C>G	p.Gln1311Glu	missense	Exon 30 of 32	NP_001398074.1	A0A7P0TAK3
	WDR62	NM_173636.5		c.3931C>G	p.Gln1311Glu	missense	Exon 30 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.3946C>G	p.Gln1316Glu	missense	Exon 30 of 32	ENSP00000384792.1	O43379-4
	WDR62	ENST00000587391.6	TSL:1	n.*3806C>G		non_coding_transcript_exon	Exon 28 of 30	ENSP00000465525.1	O43379-2
	WDR62	ENST00000587391.6	TSL:1	n.*3806C>G		3_prime_UTR	Exon 28 of 30	ENSP00000465525.1	O43379-2

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 618 AN: 152062 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00690

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00401 AC: 997 AN: 248818 AF XY: 0.00398

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00419

Gnomad ASJ exome AF: 0.00329

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000664

Gnomad NFE exome AF: 0.00658

Gnomad OTH exome AF: 0.00573

GnomAD4 exome AF: 0.00578 AC: 8425 AN: 1458268 Hom.: 24 Cov.: 36 AF XY: 0.00555 AC XY: 4030 AN XY: 725558

African (AFR) AF: 0.000837 AC: 28 AN: 33464

American (AMR) AF: 0.00474 AC: 212 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00356 AC: 93 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86236

European-Finnish (FIN) AF: 0.000895 AC: 45 AN: 50262

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5764

European-Non Finnish (NFE) AF: 0.00698 AC: 7755 AN: 1111676

Other (OTH) AF: 0.00461 AC: 278 AN: 60348

GnomAD4 genome AF: 0.00405 AC: 617 AN: 152184 Hom.: 2 Cov.: 33 AF XY: 0.00339 AC XY: 252 AN XY: 74406

African (AFR) AF: 0.00154 AC: 64 AN: 41524

American (AMR) AF: 0.00327 AC: 50 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00688 AC: 468 AN: 67984

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00598 Hom.: 2

Bravo AF: 0.00466

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00384 AC: 466

EpiCase AF: 0.00802

EpiControl AF: 0.00907

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.5
DANN	Benign	0.32
DEOGEN2	Benign	0.00071	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.45
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.024
Sift	Benign	0.48	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.14
MVP		0.38
MPC		0.24
ClinPred		0.0033	T
GERP RS		1.5
Varity_R		0.069
gMVP		0.11
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs35811023; hg19: chr19-36594676; COSMIC: COSV105820141;