10-114290249-A-G

Variant names:

• chr10-114290249-A-G
• rs11196686
• NM_001272046.2:c.2132A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001272046.2(VWA2):​c.2132A>G​(p.Gln711Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0823 in 1,550,356 control chromosomes in the GnomAD database, including 6,810 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.084 (694 hom., cov: 32)
  • Exomes 𝑓: 0.082 (6116 hom.)
• Consequence: VWA2 NM_001272046.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.283
• Publications: 11 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026874244).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWA2	NM_001272046.2	c.2132A>G	p.Gln711Arg	missense_variant	Exon 13 of 14	ENST00000392982.8	NP_001258975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VWA2	ENST00000392982.8	c.2132A>G	p.Gln711Arg	missense_variant	Exon 13 of 14	1	NM_001272046.2	ENSP00000376708.3

Frequencies

GnomAD3 genomes AF: 0.0844 AC: 12840 AN: 152078 Hom.: 694 Cov.: 32

Gnomad AFR AF: 0.0791

Gnomad AMI AF: 0.0791

Gnomad AMR AF: 0.0669

Gnomad ASJ AF: 0.0893

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.0978

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.0687

Gnomad OTH AF: 0.0788

GnomAD2 exomes AF: 0.105 AC: 15621 AN: 149036 AF XY: 0.107

Gnomad AFR exome AF: 0.0810

Gnomad AMR exome AF: 0.0750

Gnomad ASJ exome AF: 0.0879

Gnomad EAS exome AF: 0.279

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.0685

Gnomad OTH exome AF: 0.0858

GnomAD4 exome AF: 0.0821 AC: 114828 AN: 1398160 Hom.: 6116 Cov.: 31 AF XY: 0.0846 AC XY: 58340 AN XY: 689602

African (AFR) AF: 0.0764 AC: 2415 AN: 31596

American (AMR) AF: 0.0729 AC: 2604 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.0915 AC: 2304 AN: 25178

East Asian (EAS) AF: 0.285 AC: 10185 AN: 35716

South Asian (SAS) AF: 0.159 AC: 12631 AN: 79222

European-Finnish (FIN) AF: 0.103 AC: 4966 AN: 48168

Middle Eastern (MID) AF: 0.0695 AC: 396 AN: 5698

European-Non Finnish (NFE) AF: 0.0688 AC: 74192 AN: 1078884

Other (OTH) AF: 0.0885 AC: 5135 AN: 57994

GnomAD4 genome AF: 0.0843 AC: 12833 AN: 152196 Hom.: 694 Cov.: 32 AF XY: 0.0884 AC XY: 6580 AN XY: 74408

African (AFR) AF: 0.0790 AC: 3282 AN: 41532

American (AMR) AF: 0.0667 AC: 1020 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0893 AC: 310 AN: 3472

East Asian (EAS) AF: 0.275 AC: 1414 AN: 5140

South Asian (SAS) AF: 0.174 AC: 841 AN: 4822

European-Finnish (FIN) AF: 0.0978 AC: 1038 AN: 10612

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0687 AC: 4675 AN: 68012

Other (OTH) AF: 0.0789 AC: 167 AN: 2116

Alfa AF: 0.0763 Hom.: 1104

Bravo AF: 0.0810

TwinsUK AF: 0.0596 AC: 221

ALSPAC AF: 0.0680 AC: 262

ExAC AF: 0.0971 AC: 2132

Asia WGS AF: 0.193 AC: 669 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.20
DANN	Benign	0.61
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.012	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.47	N
PhyloP100		-0.28
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.054
Sift	Benign	0.81	T
Sift4G	Benign	1.0	T
Vest4		0.0050
ClinPred		0.0068	T
GERP RS		1.7
Varity_R		0.032
gMVP		0.46
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs11196686; hg19: chr10-116050008; COSMIC: COSV53904796; COSMIC: COSV53904796;