Variant chrX-55002275-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_014481.4(APEX2):c.266A>G(p.Asn89Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000166 in 1,202,865 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 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: 𝑓 0.000089 ( 0 hom., 3 hem., cov: 24)

Exomes 𝑓: 0.0000092 ( 0 hom. 2 hem. )

Consequence

APEX2
NM_014481.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.343

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:

APEX2 (HGNC:):

APEX2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019601256).

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APEX2	NM_014481.4 linkuse as main transcript	c.266A>G	p.Asn89Ser	missense_variant	3/6	ENST00000374987.4	NP_055296.2	Q9UBZ4E5KN95
APEX2	NM_001271748.2 linkuse as main transcript	c.-92+646A>G		intron_variant			NP_001258677.1	B7ZA71B4DWI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APEX2	ENST00000374987.4 linkuse as main transcript	c.266A>G	p.Asn89Ser	missense_variant	3/6	1	NM_014481.4	ENSP00000364126.3		Q9UBZ4
APEX2	ENST00000471758.1 linkuse as main transcript	n.271+646A>G		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000890

AC:

AN:

112310

Hom.:

Cov.:

AF XY:

0.0000870

AC XY:

AN XY:

34482

show subpopulations

Gnomad AFR

AF:

0.000292

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000118

AC:

AN:

169154

Hom.:

AF XY:

0.00

AC XY:

AN XY:

55162

show subpopulations

Gnomad AFR exome

AF:

0.000154

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000917

AC:

AN:

1090555

Hom.:

Cov.:

AF XY:

0.00000559

AC XY:

AN XY:

357537

show subpopulations

Gnomad4 AFR exome

AF:

0.000305

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:

0.00000119

Gnomad4 OTH exome

AF:

0.0000219

GnomAD4 genome

AF:

0.0000890

AC:

AN:

112310

Hom.:

Cov.:

AF XY:

0.0000870

AC XY:

AN XY:

34482

show subpopulations

Gnomad4 AFR

AF:

0.000292

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000140

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.47

DANN

Benign

0.67

DEOGEN2

Benign

0.15

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.52

M_CAP

Benign

0.0072

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.7

PrimateAI

Benign

0.26

PROVEAN

Benign

0.72

REVEL

Benign

0.15

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.016

MVP

0.32

MPC

0.12

ClinPred

0.015

GERP RS

4.4

Varity_R

0.035

gMVP

0.30

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over