NM_004039.3:c.292G>T

Variant names:

• chr15-60361006-C-A
• rs17845226
• NM_004039.3:c.292G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004039.3(ANXA2):​c.292G>T​(p.Val98Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,613,228 control chromosomes in the GnomAD database, including 12,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (733 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11370 hom.)
• Consequence: ANXA2 NM_004039.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.38
• Publications: 24 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002002865).
• BP6: Variant 15-60361006-C-A is Benign according to our data. Variant chr15-60361006-C-A is described in ClinVar as Benign. ClinVar VariationId is 1238049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004039.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANXA2	NM_004039.3	MANE Select	c.292G>T	p.Val98Leu	missense	Exon 5 of 13	NP_004030.1
	ANXA2	NM_001002858.3		c.346G>T	p.Val116Leu	missense	Exon 5 of 13	NP_001002858.1
	ANXA2	NM_001002857.2		c.292G>T	p.Val98Leu	missense	Exon 6 of 14	NP_001002857.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANXA2	ENST00000451270.7	TSL:1 MANE Select	c.292G>T	p.Val98Leu	missense	Exon 5 of 13	ENSP00000387545.3
	ANXA2	ENST00000332680.8	TSL:1	c.346G>T	p.Val116Leu	missense	Exon 5 of 13	ENSP00000346032.3
	ANXA2	ENST00000396024.7	TSL:1	c.292G>T	p.Val98Leu	missense	Exon 6 of 14	ENSP00000379342.3

Frequencies

GnomAD3 genomes AF: 0.0857 AC: 13041 AN: 152148 Hom.: 733 Cov.: 33

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0797

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0481

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.0855

GnomAD2 exomes AF: 0.0919 AC: 23107 AN: 251394 AF XY: 0.0948

Gnomad AFR exome AF: 0.0208

Gnomad AMR exome AF: 0.0555

Gnomad ASJ exome AF: 0.139

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0944

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.119 AC: 173316 AN: 1460962 Hom.: 11370 Cov.: 30 AF XY: 0.117 AC XY: 84766 AN XY: 726842

African (AFR) AF: 0.0198 AC: 663 AN: 33474

American (AMR) AF: 0.0577 AC: 2580 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 3609 AN: 26134

East Asian (EAS) AF: 0.000453 AC: 18 AN: 39698

South Asian (SAS) AF: 0.0515 AC: 4439 AN: 86222

European-Finnish (FIN) AF: 0.0967 AC: 5165 AN: 53404

Middle Eastern (MID) AF: 0.112 AC: 647 AN: 5766

European-Non Finnish (NFE) AF: 0.135 AC: 149558 AN: 1111174

Other (OTH) AF: 0.110 AC: 6637 AN: 60378

GnomAD4 genome AF: 0.0856 AC: 13036 AN: 152266 Hom.: 733 Cov.: 33 AF XY: 0.0827 AC XY: 6156 AN XY: 74458

African (AFR) AF: 0.0226 AC: 941 AN: 41558

American (AMR) AF: 0.0796 AC: 1217 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 484 AN: 3470

East Asian (EAS) AF: 0.000770 AC: 4 AN: 5192

South Asian (SAS) AF: 0.0487 AC: 235 AN: 4824

European-Finnish (FIN) AF: 0.100 AC: 1060 AN: 10600

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8837 AN: 68004

Other (OTH) AF: 0.0846 AC: 179 AN: 2116

Alfa AF: 0.111 Hom.: 514

Bravo AF: 0.0818

TwinsUK AF: 0.134 AC: 497

ALSPAC AF: 0.126 AC: 485

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.133 AC: 1144

ExAC AF: 0.0936 AC: 11367

Asia WGS AF: 0.0240 AC: 83 AN: 3478

EpiCase AF: 0.134

EpiControl AF: 0.138

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.053
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.96	T
PhyloP100		2.4
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.13
Sift	Benign	0.33	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.24		Gain of disorder (P = 0.0627)
MPC		0.13
ClinPred		0.0081	T
GERP RS		5.4
Varity_R		0.21
gMVP		0.49
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17845226; hg19: chr15-60653205; COSMIC: COSV60316858; COSMIC: COSV60316858;