10-114284966-C-T

Position:

• chr10-114284966-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001272046.2(VWA2):​c.993C>T​(p.Asn331Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00436 in 1,596,234 control chromosomes in the GnomAD database, including 248 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (118 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (130 hom.)
• Consequence: VWA2 NM_001272046.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.759

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]

AFAP1L2 (HGNC:25901): (actin filament associated protein 1 like 2) Enables SH2 domain binding activity; SH3 domain binding activity; and protein tyrosine kinase activator activity. Involved in several processes, including positive regulation of epidermal growth factor receptor signaling pathway; regulation of gene expression; and regulation of mitotic cell cycle. Located in cytosol and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

VWA2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018101931).
• BP6: Variant 10-114284966-C-T is Benign according to our data. Variant chr10-114284966-C-T is described in ClinVar as [Benign]. Clinvar id is 769372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.759 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VWA2	NM_001272046.2	c.993C>T	p.Asn331Asn	synonymous_variant	10/14	ENST00000392982.8	NP_001258975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VWA2	ENST00000392982.8	c.993C>T	p.Asn331Asn	synonymous_variant	10/14	1	NM_001272046.2	ENSP00000376708.3
VWA2	ENST00000603594.2	c.77C>T	p.Thr26Ile	missense_variant	9/11	2		ENSP00000473752.2
VWA2	ENST00000298715.8	n.1243C>T		non_coding_transcript_exon_variant	10/12	2

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3463 AN: 152194 Hom.: 118 Cov.: 33

Gnomad AFR AF: 0.0774

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.00571 AC: 1296 AN: 226800 Hom.: 39 AF XY: 0.00420 AC XY: 517 AN XY: 122976

Gnomad AFR exome AF: 0.0793

Gnomad AMR exome AF: 0.00375

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000366

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000289

Gnomad OTH exome AF: 0.00239

GnomAD4 exome AF: 0.00241 AC: 3487 AN: 1443922 Hom.: 130 Cov.: 31 AF XY: 0.00211 AC XY: 1512 AN XY: 717380

Gnomad4 AFR exome AF: 0.0820

Gnomad4 AMR exome AF: 0.00488

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000205

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000232

Gnomad4 OTH exome AF: 0.00551

GnomAD4 genome AF: 0.0228 AC: 3471 AN: 152312 Hom.: 118 Cov.: 33 AF XY: 0.0219 AC XY: 1634 AN XY: 74476

Gnomad4 AFR AF: 0.0774

Gnomad4 AMR AF: 0.0123

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.00682 Hom.: 43

Bravo AF: 0.0258

ESP6500AA AF: 0.0781 AC: 344

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00694 AC: 843

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 20, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	9.5
DANN	Benign	0.63
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0018	T
Sift4G	Uncertain	0.028	D
Polyphen		0.36	B
Vest4		0.14
MVP		0.31
GERP RS		5.5

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

LitVar

Other links and lift over

dbSNP: rs11817946; hg19: chr10-116044725;