Genetic Variant VANGL2:p.Arg353Cys (chr1-160421171-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_020335.3(VANGL2):c.1057C>T(p.Arg353Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

VANGL2
NM_020335.3 missense

Scores

Clinical Significance

risk factor no assertion criteria provided O:1

Conservation

PhyloP100: 1.09

Publications

10 publications found

Variant links:

Genes affected

VANGL2 (HGNC:15511): (VANGL planar cell polarity protein 2) The protein encoded by this gene is a membrane protein involved in the regulation of planar cell polarity, especially in the stereociliary bundles of the cochlea. The encoded protein transmits directional signals to individual cells or groups of cells in epithelial sheets. This protein is also involved in the development of the neural plate. [provided by RefSeq, Sep 2011]

VANGL2 Gene-Disease associations (from GenCC):

neural tube defects, susceptibility to
Inheritance: AD, Unknown Classification: MODERATE, LIMITED Submitted by: Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)

VANGL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.904

BS2

High AC in GnomAdExome4 at 10 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VANGL2	NM_020335.3 link	c.1057C>T	p.Arg353Cys	missense_variant	Exon 6 of 8	ENST00000368061.3	NP_065068.1	Q9ULK5A8K4L6
VANGL2	XM_005245357.2 link	c.1057C>T	p.Arg353Cys	missense_variant	Exon 7 of 9		XP_005245414.1	Q9ULK5
VANGL2	XM_011509804.2 link	c.1057C>T	p.Arg353Cys	missense_variant	Exon 6 of 8		XP_011508106.1	Q9ULK5
VANGL2	XM_047426020.1 link	c.1057C>T	p.Arg353Cys	missense_variant	Exon 6 of 8		XP_047281976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VANGL2	ENST00000368061.3 link	c.1057C>T	p.Arg353Cys	missense_variant	Exon 6 of 8	2	NM_020335.3	ENSP00000357040.2	Q9ULK5
VANGL2	ENST00000696602.2 link	c.1201C>T	p.Arg401Cys	missense_variant	Exon 6 of 8			ENSP00000512747.1	A0A8Q3SIN7
VANGL2	ENST00000483408.1 link	n.237C>T		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000797

AC:

AN:

250846

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461290

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726940

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53196

Middle Eastern (MID)

AF:

0.000182

AC:

AN:

5494

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111984

Other (OTH)

AF:

0.0000166

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Neural tube defects, susceptibility to

Other:1

Jun 10, 2010

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.90

MetaSVM

Uncertain

0.48

MutationAssessor

Uncertain

2.5

PhyloP100

1.1

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.88

MutPred

0.57

Gain of methylation at K354 (P = 0.0157);

MVP

0.88

MPC

1.7

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.69

gMVP

0.73

Mutation Taster

=54/46

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over