rs12086448

Variant names:

• chr1-160424115-A-G
• rs12086448
• NM_020335.3:c.1137A>G

Variant summary

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

The NM_020335.3(VANGL2):​c.1137A>G​(p.Lys379Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.532 in 1,613,826 control chromosomes in the GnomAD database, including 231,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26727 hom., cov: 31)
  • Exomes 𝑓: 0.53 (205157 hom.)
• Consequence: VANGL2 NM_020335.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.12
• Publications: 34 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 1-160424115-A-G is Benign according to our data. Variant chr1-160424115-A-G is described in ClinVar as Benign. ClinVar VariationId is 1684206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.12 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020335.3. 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
	VANGL2	NM_020335.3	MANE Select	c.1137A>G	p.Lys379Lys	synonymous	Exon 7 of 8	NP_065068.1	Q9ULK5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VANGL2	ENST00000368061.3	TSL:2 MANE Select	c.1137A>G	p.Lys379Lys	synonymous	Exon 7 of 8	ENSP00000357040.2	Q9ULK5
	VANGL2	ENST00000696602.2		c.1281A>G	p.Lys427Lys	synonymous	Exon 7 of 8	ENSP00000512747.1	A0A8Q3SIN7
	VANGL2	ENST00000483408.1	TSL:3	n.317A>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.579 AC: 88005 AN: 151872 Hom.: 26713 Cov.: 31

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.489

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.375

Gnomad SAS AF: 0.616

Gnomad FIN AF: 0.482

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.567

GnomAD2 exomes AF: 0.511 AC: 128496 AN: 251378 AF XY: 0.516

Gnomad AFR exome AF: 0.768

Gnomad AMR exome AF: 0.380

Gnomad ASJ exome AF: 0.476

Gnomad EAS exome AF: 0.367

Gnomad FIN exome AF: 0.483

Gnomad NFE exome AF: 0.520

Gnomad OTH exome AF: 0.503

GnomAD4 exome AF: 0.527 AC: 769714 AN: 1461836 Hom.: 205157 Cov.: 82 AF XY: 0.528 AC XY: 383723 AN XY: 727214

African (AFR) AF: 0.773 AC: 25868 AN: 33480

American (AMR) AF: 0.399 AC: 17837 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 12428 AN: 26136

East Asian (EAS) AF: 0.380 AC: 15094 AN: 39698

South Asian (SAS) AF: 0.605 AC: 52157 AN: 86258

European-Finnish (FIN) AF: 0.476 AC: 25420 AN: 53416

Middle Eastern (MID) AF: 0.525 AC: 3028 AN: 5768

European-Non Finnish (NFE) AF: 0.527 AC: 586126 AN: 1111964

Other (OTH) AF: 0.526 AC: 31756 AN: 60394

GnomAD4 genome AF: 0.579 AC: 88064 AN: 151990 Hom.: 26727 Cov.: 31 AF XY: 0.576 AC XY: 42778 AN XY: 74272

African (AFR) AF: 0.764 AC: 31645 AN: 41440

American (AMR) AF: 0.489 AC: 7470 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1660 AN: 3472

East Asian (EAS) AF: 0.375 AC: 1937 AN: 5160

South Asian (SAS) AF: 0.615 AC: 2956 AN: 4808

European-Finnish (FIN) AF: 0.482 AC: 5089 AN: 10564

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.521 AC: 35411 AN: 67948

Other (OTH) AF: 0.565 AC: 1192 AN: 2108

Alfa AF: 0.541 Hom.: 21480

Bravo AF: 0.585

Asia WGS AF: 0.525 AC: 1824 AN: 3478

EpiCase AF: 0.528

EpiControl AF: 0.527

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Neural tube defect (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.63
PhyloP100		2.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12086448; hg19: chr1-160393905; COSMIC: COSV63604186;