1-160419539-C-T

Variant names:

• chr1-160419539-C-T
• NM_020335.3:c.730C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020335.3(VANGL2):​c.730C>T​(p.Pro244Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,448,678 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VANGL2 NM_020335.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.68

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VANGL2	NM_020335.3	c.730C>T	p.Pro244Ser	missense_variant	Exon 4 of 8	ENST00000368061.3	NP_065068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VANGL2	ENST00000368061.3	c.730C>T	p.Pro244Ser	missense_variant	Exon 4 of 8	2	NM_020335.3	ENSP00000357040.2
VANGL2	ENST00000696602.1	c.874C>T	p.Pro292Ser	missense_variant	Exon 4 of 8			ENSP00000512747.1
VANGL2	ENST00000483408.1	n.47C>T		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1448678 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 721116

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.730C>T (p.P244S) alteration is located in exon 4 (coding exon 3) of the VANGL2 gene. This alteration results from a C to T substitution at nucleotide position 730, causing the proline (P) at amino acid position 244 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.022	D
Sift4G	Benign	0.12	T
Polyphen		0.043	B
Vest4		0.49
MutPred		0.88		Gain of MoRF binding (P = 0.0737);
MVP		0.30
MPC		0.61
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.57
gMVP		0.81

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-160389329;