rs2301734

Variant names:

• chr19-36084743-G-A
• rs2301734
• NM_001083961.2:c.1641G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-36084743-G-A
• chr19-36084743-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001083961.2(WDR62):​c.1641G>A​(p.Thr547Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,612,594 control chromosomes in the GnomAD database, including 30,757 homozygotes. In-silico tool predicts 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T547T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (2170 hom., cov: 31)
  • Exomes 𝑓: 0.19 (28587 hom.)
• Consequence: WDR62 NM_001083961.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.00002623
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.64
• Publications: 21 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-36084743-G-A is Benign according to our data. Variant chr19-36084743-G-A is described in ClinVar as Benign. ClinVar VariationId is 160252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.203 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.1641G>A	p.Thr547Thr	splice_region synonymous	Exon 12 of 32	NP_001077430.1	O43379-4
	WDR62	NM_001411145.1		c.1626G>A	p.Thr542Thr	splice_region synonymous	Exon 12 of 32	NP_001398074.1	A0A7P0TAK3
	WDR62	NM_173636.5		c.1641G>A	p.Thr547Thr	splice_region synonymous	Exon 12 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.1641G>A	p.Thr547Thr	splice_region synonymous	Exon 12 of 32	ENSP00000384792.1	O43379-4
	WDR62	ENST00000587391.6	TSL:1	n.*331G>A		splice_region non_coding_transcript_exon	Exon 13 of 30	ENSP00000465525.1	O43379-2
	WDR62	ENST00000587391.6	TSL:1	n.*331G>A		3_prime_UTR	Exon 13 of 30	ENSP00000465525.1	O43379-2

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22814 AN: 151936 Hom.: 2169 Cov.: 31

Gnomad AFR AF: 0.0378

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.160

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.157

GnomAD2 exomes AF: 0.180 AC: 44946 AN: 250222 AF XY: 0.185

Gnomad AFR exome AF: 0.0350

Gnomad AMR exome AF: 0.150

Gnomad ASJ exome AF: 0.223

Gnomad EAS exome AF: 0.194

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.198

GnomAD4 exome AF: 0.195 AC: 284616 AN: 1460538 Hom.: 28587 Cov.: 33 AF XY: 0.195 AC XY: 141911 AN XY: 726518

African (AFR) AF: 0.0318 AC: 1065 AN: 33476

American (AMR) AF: 0.150 AC: 6693 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 5999 AN: 26134

East Asian (EAS) AF: 0.177 AC: 7035 AN: 39696

South Asian (SAS) AF: 0.182 AC: 15661 AN: 86230

European-Finnish (FIN) AF: 0.171 AC: 9017 AN: 52612

Middle Eastern (MID) AF: 0.229 AC: 1302 AN: 5676

European-Non Finnish (NFE) AF: 0.204 AC: 226232 AN: 1111644

Other (OTH) AF: 0.192 AC: 11612 AN: 60352

GnomAD4 genome AF: 0.150 AC: 22812 AN: 152056 Hom.: 2170 Cov.: 31 AF XY: 0.149 AC XY: 11071 AN XY: 74322

African (AFR) AF: 0.0377 AC: 1564 AN: 41508

American (AMR) AF: 0.157 AC: 2397 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 794 AN: 3466

East Asian (EAS) AF: 0.182 AC: 937 AN: 5146

South Asian (SAS) AF: 0.169 AC: 815 AN: 4816

European-Finnish (FIN) AF: 0.160 AC: 1689 AN: 10572

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 14018 AN: 67968

Other (OTH) AF: 0.158 AC: 333 AN: 2106

Alfa AF: 0.184 Hom.: 8248

Bravo AF: 0.145

Asia WGS AF: 0.161 AC: 561 AN: 3478

EpiCase AF: 0.206

EpiControl AF: 0.212

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	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
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.1
DANN	Benign	0.72
PhyloP100		-1.6
PromoterAI		0.061	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=66/34	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.018
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: rs2301734; hg19: chr19-36575645; COSMIC: COSV54333037; COSMIC: COSV54333037;