Genetic Variant APEX2:p.Asn271Lys (chrX-55006691-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_014481.4(APEX2):c.813C>A(p.Asn271Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,166,450 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000059 ( 0 hom. 14 hem. )

Consequence

APEX2
NM_014481.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.37

Publications

1 publications found

Variant links:

Genes affected

APEX2 (HGNC:17889): (apurinic/apyrimidinic endodeoxyribonuclease 2) Apurinic/apyrimidinic (AP) sites occur frequently in DNA molecules by spontaneous hydrolysis, by DNA damaging agents or by DNA glycosylases that remove specific abnormal bases. AP sites are pre-mutagenic lesions that can prevent normal DNA replication so the cell contains systems to identify and repair such sites. Class II AP endonucleases cleave the phosphodiester backbone 5' to the AP site. This gene encodes a protein shown to have a weak class II AP endonuclease activity. Most of the encoded protein is located in the nucleus but some is also present in mitochondria. This protein may play an important role in both nuclear and mitochondrial base excision repair. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2012]

APEX2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Hemizygotes in GnomAd4 at 3 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014481.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APEX2	NM_014481.4	MANE Select	c.813C>A	p.Asn271Lys	missense	Exon 6 of 6	NP_055296.2
	APEX2	NM_001271748.2		c.300C>A	p.Asn100Lys	missense	Exon 5 of 5	NP_001258677.1	B7ZA71

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APEX2	ENST00000374987.4	TSL:1 MANE Select	c.813C>A	p.Asn271Lys	missense	Exon 6 of 6	ENSP00000364126.3	Q9UBZ4
APEX2	ENST00000919358.1		c.768C>A	p.Asn256Lys	missense	Exon 6 of 6	ENSP00000589417.1
APEX2	ENST00000886736.1		c.666C>A	p.Asn222Lys	missense	Exon 5 of 5	ENSP00000556795.1

Frequencies

GnomAD3 genomes

AF:

0.0000979

AC:

AN:

112359

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00226

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000940

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000115

AC:

AN:

139157

AF XY:

0.0000807

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00192

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000112

Gnomad OTH exome

AF:

0.000296

GnomAD4 exome

AF:

0.0000588

AC:

AN:

1054039

Hom.:

Cov.:

AF XY:

0.0000418

AC XY:

AN XY:

335139

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25307

American (AMR)

AF:

0.00

AC:

AN:

30239

Ashkenazi Jewish (ASJ)

AF:

0.00186

AC:

AN:

16700

East Asian (EAS)

AF:

0.00

AC:

AN:

29544

South Asian (SAS)

AF:

0.00

AC:

AN:

47101

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38852

Middle Eastern (MID)

AF:

0.000254

AC:

AN:

3937

European-Non Finnish (NFE)

AF:

0.0000281

AC:

AN:

818274

Other (OTH)

AF:

0.000159

AC:

AN:

44085

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000979

AC:

AN:

112411

Hom.:

Cov.:

AF XY:

0.0000868

AC XY:

AN XY:

34547

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30998

American (AMR)

AF:

0.00

AC:

AN:

10717

Ashkenazi Jewish (ASJ)

AF:

0.00226

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3551

South Asian (SAS)

AF:

0.00

AC:

AN:

2692

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6175

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0000940

AC:

AN:

53197

Other (OTH)

AF:

0.00

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000474

Hom.:

Bravo

AF:

0.000102

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000745

AC:

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

Pathogenic

0.82

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.64

MetaRNN

Uncertain

0.52

MetaSVM

Benign

-0.31

MutationAssessor

Pathogenic

3.3

PhyloP100

1.4

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.7

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0070

Polyphen

0.73

Vest4

0.83

MutPred

0.62

Gain of solvent accessibility (P = 0.0086)

MVP

0.72

MPC

0.67

ClinPred

0.50

GERP RS

2.5

Varity_R

0.92

gMVP

0.97

Mutation Taster

=73/27

polymorphism

(source)

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

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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