Genetic Variant APEX2:p.His239His (chrX-55006595-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_014481.4(APEX2):c.717T>C(p.His239His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000617 in 1,146,618 control chromosomes in the GnomAD database, including 2 homozygotes. There are 266 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., 15 hem., cov: 22)

Exomes 𝑓: 0.00064 ( 2 hom. 251 hem. )

Consequence

APEX2
NM_014481.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.41

Publications

0 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BS2

High Hemizygotes in GnomAd4 at 15 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.717T>C	p.His239His	synonymous	Exon 6 of 6	NP_055296.2
	APEX2	NM_001271748.2		c.204T>C	p.His68His	synonymous	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.717T>C	p.His239His	synonymous	Exon 6 of 6	ENSP00000364126.3	Q9UBZ4
APEX2	ENST00000919358.1		c.672T>C	p.His224His	synonymous	Exon 6 of 6	ENSP00000589417.1
APEX2	ENST00000886736.1		c.570T>C	p.His190His	synonymous	Exon 5 of 5	ENSP00000556795.1

Frequencies

GnomAD3 genomes

AF:

0.000402

AC:

AN:

111873

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000282

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00114

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000677

Gnomad OTH

AF:

0.000668

GnomAD2 exomes

AF:

0.000687

AC:

AN:

128166

AF XY:

0.000966

show subpopulations

Gnomad AFR exome

AF:

0.000252

Gnomad AMR exome

AF:

0.000221

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000247

Gnomad NFE exome

AF:

0.000703

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000640

AC:

662

AN:

1034692

Hom.:

Cov.:

AF XY:

0.000760

AC XY:

251

AN XY:

330436

show subpopulations

African (AFR)

AF:

0.0000824

AC:

AN:

24262

American (AMR)

AF:

0.000235

AC:

AN:

25570

Ashkenazi Jewish (ASJ)

AF:

0.0000654

AC:

AN:

15296

East Asian (EAS)

AF:

0.00

AC:

AN:

29447

South Asian (SAS)

AF:

0.00390

AC:

173

AN:

44393

European-Finnish (FIN)

AF:

0.000236

AC:

AN:

38181

Middle Eastern (MID)

AF:

0.00521

AC:

AN:

3840

European-Non Finnish (NFE)

AF:

0.000501

AC:

406

AN:

810470

Other (OTH)

AF:

0.00104

AC:

AN:

43233

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

101

126

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000402

AC:

AN:

111926

Hom.:

Cov.:

AF XY:

0.000440

AC XY:

AN XY:

34096

show subpopulations

African (AFR)

AF:

0.0000650

AC:

AN:

30784

American (AMR)

AF:

0.000282

AC:

AN:

10652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3537

South Asian (SAS)

AF:

0.00114

AC:

AN:

2630

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6127

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.000678

AC:

AN:

53134

Other (OTH)

AF:

0.000660

AC:

AN:

1516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.000220

Hom.:

Bravo

AF:

0.000389

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.88

(source)

DANN

Benign

0.66

PhyloP100

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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