10-114278053-A-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001272046.2(VWA2):c.700+6A>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,608,010 control chromosomes in the GnomAD database, including 129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (6 hom., cov: 32)
  • Exomes 𝑓: 0.011 (123 hom.)
• Consequence: VWA2 NM_001272046.2 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00006753
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.511

Genes affected

VWA2 (HGNC:24709): (von Willebrand factor A domain containing 2) This gene encodes a member of the von Willebrand factor A-like domain protein superfamily. The encoded protein is localized to the extracellular matrix and may serve as a structural component in basement membranes or in anchoring structures on scaffolds of collagen VII or fibrillin. This gene has been linked to type 1A diabetes and is a candidate serological marker for colon cancer. [provided by RefSeq, Jan 2013]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-114278053-A-C is Benign according to our data. Variant chr10-114278053-A-C is described in ClinVar as [Benign]. Clinvar id is 784517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VWA2	NM_001272046.2	c.700+6A>C		splice_donor_region_variant, intron_variant		ENST00000392982.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VWA2	ENST00000392982.8	c.700+6A>C		splice_donor_region_variant, intron_variant		1	NM_001272046.2	P1
VWA2	ENST00000603594.2	c.-217+6A>C		splice_donor_region_variant, intron_variant		2
VWA2	ENST00000298715.8	n.950+6A>C		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00701 AC: 1067 AN: 152172 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00962

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00932

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00675 AC: 1681 AN: 249140 Hom.: 10 AF XY: 0.00706 AC XY: 953 AN XY: 134912

Gnomad AFR exome AF: 0.00198

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00936

Gnomad FIN exome AF: 0.00169

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00657

GnomAD4 exome AF: 0.0110 AC: 15960 AN: 1455720 Hom.: 123 Cov.: 31 AF XY: 0.0109 AC XY: 7856 AN XY: 722974

Gnomad4 AFR exome AF: 0.00183

Gnomad4 AMR exome AF: 0.00450

Gnomad4 ASJ exome AF: 0.000422

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0102

Gnomad4 FIN exome AF: 0.00194

Gnomad4 NFE exome AF: 0.0128

Gnomad4 OTH exome AF: 0.00845

GnomAD4 genome AF: 0.00702 AC: 1069 AN: 152290 Hom.: 6 Cov.: 32 AF XY: 0.00705 AC XY: 525 AN XY: 74480

Gnomad4 AFR AF: 0.00192

Gnomad4 AMR AF: 0.00961

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00974

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.0113

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00808 Hom.: 0

Bravo AF: 0.00746

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0101

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

VWA2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 13, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.45
Dann	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000068
dbscSNV1_RF	Benign	0.0060
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

LitVar

Other links and lift over

dbSNP: rs192338744; hg19: chr10-116037812;