rs17851503

Variant names:

• chr19-36103951-G-A
• rs17851503
• NM_001083961.2:c.4123G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001083961.2(WDR62):​c.4123G>A​(p.Gly1375Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0435 in 1,598,538 control chromosomes in the GnomAD database, including 1,760 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (140 hom., cov: 33)
  • Exomes 𝑓: 0.044 (1620 hom.)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0300
• Publications: 16 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=0.0016288757).
• BP6: Variant 19-36103951-G-A is Benign according to our data. Variant chr19-36103951-G-A is described in ClinVar as Benign. ClinVar VariationId is 160298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0611 is higher than 0.05.

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.4123G>A	p.Gly1375Ser	missense	Exon 30 of 32	NP_001077430.1	O43379-4
	WDR62	NM_001411145.1		c.4108G>A	p.Gly1370Ser	missense	Exon 30 of 32	NP_001398074.1	A0A7P0TAK3
	WDR62	NM_173636.5		c.4108G>A	p.Gly1370Ser	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.4123G>A	p.Gly1375Ser	missense	Exon 30 of 32	ENSP00000384792.1	O43379-4
	WDR62	ENST00000587391.6	TSL:1	n.*3983G>A		non_coding_transcript_exon	Exon 28 of 30	ENSP00000465525.1	O43379-2
	WDR62	ENST00000587391.6	TSL:1	n.*3983G>A		3_prime_UTR	Exon 28 of 30	ENSP00000465525.1	O43379-2

Frequencies

GnomAD3 genomes AF: 0.0351 AC: 5339 AN: 152184 Hom.: 140 Cov.: 33

Gnomad AFR AF: 0.00864

Gnomad AMI AF: 0.0582

Gnomad AMR AF: 0.0374

Gnomad ASJ AF: 0.0625

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.0486

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0497

Gnomad OTH AF: 0.0492

GnomAD2 exomes AF: 0.0380 AC: 9043 AN: 237866 AF XY: 0.0393

Gnomad AFR exome AF: 0.00738

Gnomad AMR exome AF: 0.0291

Gnomad ASJ exome AF: 0.0616

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0481

Gnomad NFE exome AF: 0.0517

Gnomad OTH exome AF: 0.0470

GnomAD4 exome AF: 0.0444 AC: 64192 AN: 1446236 Hom.: 1620 Cov.: 36 AF XY: 0.0443 AC XY: 31897 AN XY: 719846

African (AFR) AF: 0.00783 AC: 262 AN: 33456

American (AMR) AF: 0.0299 AC: 1335 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 1460 AN: 26134

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39696

South Asian (SAS) AF: 0.0224 AC: 1933 AN: 86224

European-Finnish (FIN) AF: 0.0459 AC: 1766 AN: 38466

Middle Eastern (MID) AF: 0.0668 AC: 361 AN: 5408

European-Non Finnish (NFE) AF: 0.0490 AC: 54433 AN: 1111884

Other (OTH) AF: 0.0438 AC: 2638 AN: 60254

GnomAD4 genome AF: 0.0350 AC: 5338 AN: 152302 Hom.: 140 Cov.: 33 AF XY: 0.0349 AC XY: 2599 AN XY: 74482

African (AFR) AF: 0.00864 AC: 359 AN: 41562

American (AMR) AF: 0.0373 AC: 571 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0625 AC: 217 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0216 AC: 104 AN: 4824

European-Finnish (FIN) AF: 0.0486 AC: 516 AN: 10624

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0497 AC: 3380 AN: 68024

Other (OTH) AF: 0.0487 AC: 103 AN: 2116

Alfa AF: 0.0462 Hom.: 184

Bravo AF: 0.0345

TwinsUK AF: 0.0461 AC: 171

ALSPAC AF: 0.0488 AC: 188

ESP6500AA AF: 0.00862 AC: 38

ESP6500EA AF: 0.0453 AC: 390

ExAC AF: 0.0381 AC: 4603

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.0576

EpiControl AF: 0.0601

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Microcephaly 2, primary, autosomal recessive, with or without cortical malformations (3)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.054
DANN	Benign	0.36
DEOGEN2	Benign	0.0015	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N
PhyloP100		0.030
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.017
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.022
MPC		0.22
ClinPred		0.0000096	T
GERP RS		-1.6
Varity_R		0.033
gMVP		0.097
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs17851503; hg19: chr19-36594853; COSMIC: COSV54332620;