Genetic Variant ANXA2:p.Gly12Glu (chr15-60397879-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001002858.3(ANXA2):c.35G>A(p.Gly12Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000363 in 1,378,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

ANXA2
NM_001002858.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.998

Publications

1 publications found

Variant links:

Genes affected

ANXA2 (HGNC:537): (annexin A2) This gene encodes a member of the annexin family. Members of this calcium-dependent phospholipid-binding protein family play a role in the regulation of cellular growth and in signal transduction pathways. This protein functions as an autocrine factor which heightens osteoclast formation and bone resorption. This gene has three pseudogenes located on chromosomes 4, 9 and 10, respectively. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. Annexin A2 expression has been found to correlate with resistance to treatment against various cancer forms. [provided by RefSeq, Dec 2019]

ANXA2 links:

ENSG00000306403 (HGNC:):

ENSG00000306403 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06669778).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001002858.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANXA2	NM_004039.3	MANE Select	c.-12+64G>A		intron	N/A	NP_004030.1	P07355-1
ANXA2	NM_001002858.3		c.35G>A	p.Gly12Glu	missense	Exon 1 of 13	NP_001002858.1	P07355-2
ANXA2	NM_001002857.2		c.-93+64G>A		intron	N/A	NP_001002857.1	P07355-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANXA2	ENST00000332680.8	TSL:1	c.35G>A	p.Gly12Glu	missense	Exon 1 of 13	ENSP00000346032.3	P07355-2
ANXA2	ENST00000451270.7	TSL:1 MANE Select	c.-12+64G>A		intron	N/A	ENSP00000387545.3	P07355-1
ANXA2	ENST00000396024.7	TSL:1	c.-117+64G>A		intron	N/A	ENSP00000379342.3	P07355-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00

AC:

AN:

57370

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000391

AC:

AN:

1226556

Hom.:

Cov.:

AF XY:

0.0000467

AC XY:

AN XY:

599326

show subpopulations

African (AFR)

AF:

0.0000402

AC:

AN:

24852

American (AMR)

AF:

0.00

AC:

AN:

16916

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17384

East Asian (EAS)

AF:

0.00

AC:

AN:

28658

South Asian (SAS)

AF:

0.0000377

AC:

AN:

53050

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33066

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4922

European-Non Finnish (NFE)

AF:

0.0000431

AC:

AN:

998336

Other (OTH)

AF:

0.0000405

AC:

AN:

49372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.65

CADD

Benign

5.6

(source)

DANN

Benign

0.91

Eigen

Benign

-0.94

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.32

M_CAP

Benign

0.068

MetaRNN

Benign

0.067

MetaSVM

Benign

-0.93

PhyloP100

-1.0

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.11

REVEL

Benign

0.012

Sift

Benign

0.081

Sift4G

Benign

0.30

Polyphen

0.015

Vest4

0.068

MutPred

0.26

Loss of catalytic residue at A11 (P = 0.0334)

MVP

0.13

MPC

0.18

ClinPred

0.25

GERP RS

1.4

PromoterAI

-0.022

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over