rs1008328

Variant names:

• chr19-36104534-A-C
• rs1008328
• NM_001083961.2:c.4170A>C

Your query was ambiguous. Multiple possible variants found:

• chr19-36104534-A-C
• chr19-36104534-A-G
• chr19-36104534-A-T

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.4170A>C​(p.Leu1390Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.761 in 1,613,644 control chromosomes in the GnomAD database, including 469,035 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 0.75 (42774 hom., cov: 32)
  • Exomes 𝑓: 0.76 (426261 hom.)
• Consequence: WDR62 NM_001083961.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.126
• Publications: 36 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=9.692469E-7).
• BP6: Variant 19-36104534-A-C is Benign according to our data. Variant chr19-36104534-A-C is described in ClinVar as Benign. ClinVar VariationId is 160301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.774 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.4170A>C	p.Leu1390Phe	missense	Exon 31 of 32	NP_001077430.1	O43379-4
	WDR62	NM_001411145.1		c.4155A>C	p.Leu1385Phe	missense	Exon 31 of 32	NP_001398074.1	A0A7P0TAK3
	WDR62	NM_173636.5		c.4155A>C	p.Leu1385Phe	missense	Exon 31 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.4170A>C	p.Leu1390Phe	missense	Exon 31 of 32	ENSP00000384792.1	O43379-4
	WDR62	ENST00000587391.6	TSL:1	n.*4030A>C		non_coding_transcript_exon	Exon 29 of 30	ENSP00000465525.1	O43379-2
	WDR62	ENST00000587391.6	TSL:1	n.*4030A>C		3_prime_UTR	Exon 29 of 30	ENSP00000465525.1	O43379-2

Frequencies

GnomAD3 genomes AF: 0.749 AC: 113841 AN: 151982 Hom.: 42761 Cov.: 32

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.786

Gnomad ASJ AF: 0.759

Gnomad EAS AF: 0.747

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.782

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.777

Gnomad OTH AF: 0.759

GnomAD2 exomes AF: 0.750 AC: 188442 AN: 251128 AF XY: 0.745

Gnomad AFR exome AF: 0.698

Gnomad AMR exome AF: 0.807

Gnomad ASJ exome AF: 0.760

Gnomad EAS exome AF: 0.750

Gnomad FIN exome AF: 0.770

Gnomad NFE exome AF: 0.774

Gnomad OTH exome AF: 0.764

GnomAD4 exome AF: 0.762 AC: 1114342 AN: 1461544 Hom.: 426261 Cov.: 76 AF XY: 0.759 AC XY: 551863 AN XY: 727086

African (AFR) AF: 0.700 AC: 23442 AN: 33480

American (AMR) AF: 0.806 AC: 36060 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.752 AC: 19654 AN: 26128

East Asian (EAS) AF: 0.769 AC: 30525 AN: 39700

South Asian (SAS) AF: 0.617 AC: 53253 AN: 86254

European-Finnish (FIN) AF: 0.775 AC: 41177 AN: 53152

Middle Eastern (MID) AF: 0.757 AC: 4366 AN: 5768

European-Non Finnish (NFE) AF: 0.774 AC: 860623 AN: 1111958

Other (OTH) AF: 0.749 AC: 45242 AN: 60386

GnomAD4 genome AF: 0.749 AC: 113895 AN: 152100 Hom.: 42774 Cov.: 32 AF XY: 0.748 AC XY: 55623 AN XY: 74330

African (AFR) AF: 0.699 AC: 28992 AN: 41464

American (AMR) AF: 0.786 AC: 12017 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.759 AC: 2634 AN: 3470

East Asian (EAS) AF: 0.746 AC: 3844 AN: 5152

South Asian (SAS) AF: 0.599 AC: 2889 AN: 4822

European-Finnish (FIN) AF: 0.782 AC: 8286 AN: 10594

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.777 AC: 52842 AN: 67994

Other (OTH) AF: 0.757 AC: 1601 AN: 2114

Alfa AF: 0.768 Hom.: 117215

Bravo AF: 0.751

TwinsUK AF: 0.770 AC: 2854

ALSPAC AF: 0.769 AC: 2965

ESP6500AA AF: 0.696 AC: 3066

ESP6500EA AF: 0.776 AC: 6676

ExAC AF: 0.742 AC: 90139

Asia WGS AF: 0.636 AC: 2212 AN: 3478

EpiCase AF: 0.782

EpiControl AF: 0.785

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.3
DANN	Benign	0.54
DEOGEN2	Benign	0.00089	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.083	T
MetaRNN	Benign	9.7e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.13
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.055
Sift	Benign	0.31	T
Sift4G	Benign	0.56	T
Polyphen		0.0020	B
Vest4		0.029
MutPred		0.36		Loss of phosphorylation at S1388 (P = 0.1262)
MPC		0.24
ClinPred		0.0034	T
GERP RS		2.0
Varity_R		0.047
gMVP		0.045
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: rs1008328; hg19: chr19-36595436; COSMIC: COSV54335267;