X-55002258-C-T

Variant names:

• chrX-55002258-C-T
• rs61752443
• NM_014481.4:c.249C>T

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.249C>T​(p.Ala83Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,193,051 control chromosomes in the GnomAD database, including 63 homozygotes. There are 3,697 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (4 hom., 202 hem., cov: 23)
  • Exomes 𝑓: 0.010 (59 hom. 3495 hem.)
• Consequence: APEX2 NM_014481.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.957
• Publications: 2 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 (BayesDel_noAF=-0.53).
• BP6: Variant X-55002258-C-T is Benign according to our data. Variant chrX-55002258-C-T is described in ClinVar as Benign. ClinVar VariationId is 719560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 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.249C>T	p.Ala83Ala	synonymous	Exon 3 of 6	NP_055296.2
	APEX2	NM_001271748.2		c.-92+629C>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.249C>T	p.Ala83Ala	synonymous	Exon 3 of 6	ENSP00000364126.3	Q9UBZ4
	APEX2	ENST00000919358.1		c.249C>T	p.Ala83Ala	synonymous	Exon 3 of 6	ENSP00000589417.1
	APEX2	ENST00000886736.1		c.249C>T	p.Ala83Ala	synonymous	Exon 3 of 5	ENSP00000556795.1

Frequencies

GnomAD3 genomes AF: 0.00708 AC: 796 AN: 112364 Hom.: 4 Cov.: 23

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000737

Gnomad FIN AF: 0.000969

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.00635 AC: 1006 AN: 158422 AF XY: 0.00555

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00668

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00183

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00736

GnomAD4 exome AF: 0.0104 AC: 11287 AN: 1080633 Hom.: 59 Cov.: 31 AF XY: 0.00995 AC XY: 3495 AN XY: 351239

African (AFR) AF: 0.00162 AC: 42 AN: 25890

American (AMR) AF: 0.00701 AC: 227 AN: 32403

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18042

East Asian (EAS) AF: 0.00 AC: 0 AN: 29986

South Asian (SAS) AF: 0.000896 AC: 45 AN: 50220

European-Finnish (FIN) AF: 0.00215 AC: 86 AN: 39953

Middle Eastern (MID) AF: 0.000251 AC: 1 AN: 3983

European-Non Finnish (NFE) AF: 0.0126 AC: 10529 AN: 834882

Other (OTH) AF: 0.00789 AC: 357 AN: 45274

GnomAD4 genome AF: 0.00707 AC: 795 AN: 112418 Hom.: 4 Cov.: 23 AF XY: 0.00584 AC XY: 202 AN XY: 34592

African (AFR) AF: 0.00188 AC: 58 AN: 30933

American (AMR) AF: 0.0105 AC: 113 AN: 10713

Ashkenazi Jewish (ASJ) AF: 0.000377 AC: 1 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3558

South Asian (SAS) AF: 0.000740 AC: 2 AN: 2704

European-Finnish (FIN) AF: 0.000969 AC: 6 AN: 6190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0112 AC: 597 AN: 53224

Other (OTH) AF: 0.0117 AC: 18 AN: 1538

Alfa AF: 0.00658 Hom.: 46

Bravo AF: 0.00778

ClinVar

ClinVar submissions

Significance: 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
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.5
DANN	Benign	0.72
PhyloP100		-0.96
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs61752443; hg19: chrX-55028691; COSMIC: COSV66623720; COSMIC: COSV66623720;