X-55002430-C-T

Variant names:

• chrX-55002430-C-T
• rs2301416
• NM_014481.4:c.421C>T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014481.4(APEX2):​c.421C>T​(p.Arg141Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0055 in 1,182,084 control chromosomes in the GnomAD database, including 20 homozygotes. There are 2,018 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R141W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., 81 hem., cov: 24)
  • Exomes 𝑓: 0.0058 (19 hom. 1937 hem.)
• Consequence: APEX2 NM_014481.4 missense, splice_region
• Scores: Splicing: ADA: 0.003203
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.937

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006798476).
• BP6: Variant X-55002430-C-T is Benign according to our data. Variant chrX-55002430-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 710773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 81 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APEX2	NM_014481.4	c.421C>T	p.Arg141Cys	missense_variant, splice_region_variant	Exon 3 of 6	ENST00000374987.4	NP_055296.2
APEX2	NM_001271748.2	c.-91-532C>T		intron_variant	Intron 2 of 4		NP_001258677.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APEX2	ENST00000374987.4	c.421C>T	p.Arg141Cys	missense_variant, splice_region_variant	Exon 3 of 6	1	NM_014481.4	ENSP00000364126.3
APEX2	ENST00000471758.1	n.272-532C>T		intron_variant	Intron 2 of 4	2

Frequencies

GnomAD3 genomes AF: 0.00301 AC: 340 AN: 112855 Hom.: 1 Cov.: 24 AF XY: 0.00231 AC XY: 81 AN XY: 34991

Gnomad AFR AF: 0.000548

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000926

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00167

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00176

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.00196

GnomAD3 exomes AF: 0.00316 AC: 474 AN: 149892 Hom.: 0 AF XY: 0.00310 AC XY: 140 AN XY: 45156

Gnomad AFR exome AF: 0.000475

Gnomad AMR exome AF: 0.000757

Gnomad ASJ exome AF: 0.000638

Gnomad EAS exome AF: 0.000402

Gnomad SAS exome AF: 0.0000846

Gnomad FIN exome AF: 0.00308

Gnomad NFE exome AF: 0.00560

Gnomad OTH exome AF: 0.00304

GnomAD4 exome AF: 0.00576 AC: 6161 AN: 1069173 Hom.: 19 Cov.: 30 AF XY: 0.00563 AC XY: 1937 AN XY: 343793

Gnomad4 AFR exome AF: 0.000432

Gnomad4 AMR exome AF: 0.000832

Gnomad4 ASJ exome AF: 0.000638

Gnomad4 EAS exome AF: 0.00322

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.00352

Gnomad4 NFE exome AF: 0.00681

Gnomad4 OTH exome AF: 0.00468

GnomAD4 genome AF: 0.00301 AC: 340 AN: 112911 Hom.: 1 Cov.: 24 AF XY: 0.00231 AC XY: 81 AN XY: 35057

Gnomad4 AFR AF: 0.000546

Gnomad4 AMR AF: 0.000925

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00168

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00176

Gnomad4 NFE AF: 0.00550

Gnomad4 OTH AF: 0.00194

Alfa AF: 0.00456 Hom.: 274

Bravo AF: 0.00285

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00415 AC: 12

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00580 AC: 39

ExAC AF: 0.00306 AC: 371

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 06, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.87
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.94	L
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.055
Sift	Benign	0.19	T
Sift4G	Benign	0.18	T
Polyphen		0.033	B
Vest4		0.058
MVP		0.24
MPC		0.21
ClinPred		0.0089	T
GERP RS		-0.65
Varity_R		0.12
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0032
dbscSNV1_RF	Benign	0.22
SpliceAI score (max)		0.11		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

Other links and lift over

dbSNP: rs2301416; hg19: chrX-55028863; COSMIC: COSV99055571; COSMIC: COSV99055571;