Genetic Variant NM_001272046.2:c.948C>G (chr10-114284921-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001272046.2(VWA2):c.948C>G(p.Asp316Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

VWA2
NM_001272046.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.538

Variant links:

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]

VWA2 links:

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]

AFAP1L2 links:

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ACMG classification

Classification made for transcript

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
VWA2	NM_001272046.2 link	c.948C>G	p.Asp316Glu	missense_variant	Exon 10 of 14	ENST00000392982.8	NP_001258975.1	Q5GFL6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VWA2	ENST00000392982.8 link	c.948C>G	p.Asp316Glu	missense_variant	Exon 10 of 14	1	NM_001272046.2	ENSP00000376708.3	Q5GFL6-1
VWA2	ENST00000603594.2 link	c.32C>G	p.Thr11Arg	missense_variant	Exon 9 of 11	2		ENSP00000473752.2	Q5GFL6-3
VWA2	ENST00000298715.8 link	n.1198C>G		non_coding_transcript_exon_variant	Exon 10 of 12	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000417

AC:

AN:

239534

Hom.:

AF XY:

0.00000770

AC XY:

AN XY:

129828

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000915

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1453066

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722612

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.033

DANN

Benign

0.61

DEOGEN2

Benign

0.13

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.054

LIST_S2

Benign

0.65

M_CAP

Benign

0.075

MetaRNN

Benign

0.095

MetaSVM

Benign

-0.31

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.010

REVEL

Uncertain

0.31

Sift

Benign

0.36

Sift4G

Benign

0.41

Polyphen

0.66

Vest4

0.10

MutPred

0.47

Gain of disorder (P = 0.1188);

MVP

0.12

ClinPred

0.10

GERP RS

-1.9

Varity_R

0.036

gMVP

0.32

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.34

Position offset: 49

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over