rs2301416

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-55002430-C-T
• chrX-55002430-C-G

Variant summary

Our verdict is Benign. The variant received -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. 16/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R141H) has been classified as Uncertain significance.

• 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
• Publications: 4 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 710773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 81 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.421C>T	p.Arg141Cys	missense splice_region	Exon 3 of 6	NP_055296.2
	APEX2	NM_001271748.2		c.-91-532C>T		intron	N/A	NP_001258677.1	B7ZA71

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APEX2	ENST00000374987.4	TSL:1 MANE Select	c.421C>T	p.Arg141Cys	missense splice_region	Exon 3 of 6	ENSP00000364126.3	Q9UBZ4
	APEX2	ENST00000919358.1		c.421C>T	p.Arg141*	stop_gained splice_region	Exon 3 of 6	ENSP00000589417.1
	APEX2	ENST00000886736.1		c.421C>T	p.Arg141Cys	missense splice_region	Exon 3 of 5	ENSP00000556795.1

Frequencies

GnomAD3 genomes AF: 0.00301 AC: 340 AN: 112855 Hom.: 1 Cov.: 24

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

GnomAD2 exomes AF: 0.00316 AC: 474 AN: 149892 AF XY: 0.00310

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 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

African (AFR) AF: 0.000432 AC: 11 AN: 25492

American (AMR) AF: 0.000832 AC: 25 AN: 30037

Ashkenazi Jewish (ASJ) AF: 0.000638 AC: 11 AN: 17233

East Asian (EAS) AF: 0.00322 AC: 96 AN: 29798

South Asian (SAS) AF: 0.000290 AC: 14 AN: 48320

European-Finnish (FIN) AF: 0.00352 AC: 139 AN: 39541

Middle Eastern (MID) AF: 0.000758 AC: 3 AN: 3957

European-Non Finnish (NFE) AF: 0.00681 AC: 5652 AN: 829904

Other (OTH) AF: 0.00468 AC: 210 AN: 44891

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

African (AFR) AF: 0.000546 AC: 17 AN: 31118

American (AMR) AF: 0.000925 AC: 10 AN: 10815

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00168 AC: 6 AN: 3573

South Asian (SAS) AF: 0.00 AC: 0 AN: 2732

European-Finnish (FIN) AF: 0.00176 AC: 11 AN: 6263

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.00550 AC: 293 AN: 53311

Other (OTH) AF: 0.00194 AC: 3 AN: 1547

Alfa AF: 0.00428 Hom.: 314

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

ClinVar submissions

Significance: Likely 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	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
PhyloP100		0.94
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
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

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