Genetic Variant PARP2:p.Asn58Ser (chr14-20345058-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001042618.2(PARP2):c.173A>G(p.Asn58Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PARP2
NM_001042618.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.886

Variant links:

Genes affected

PARP2 (HGNC:272): (poly(ADP-ribose) polymerase 2) This gene encodes poly(ADP-ribosyl)transferase-like 2 protein, which contains a catalytic domain and is capable of catalyzing a poly(ADP-ribosyl)ation reaction. This protein has a catalytic domain which is homologous to that of poly (ADP-ribosyl) transferase, but lacks an N-terminal DNA binding domain which activates the C-terminal catalytic domain of poly (ADP-ribosyl) transferase. The basic residues within the N-terminal region of this protein may bear potential DNA-binding properties, and may be involved in the nuclear and/or nucleolar targeting of the protein. Two alternatively spliced transcript variants encoding distinct isoforms have been found. [provided by RefSeq, Jul 2008]

PARP2 links:

ENSG00000254846 (HGNC:):

ENSG00000254846 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARP2	NM_001042618.2 link	c.173A>G	p.Asn58Ser	missense_variant	Exon 2 of 16	ENST00000429687.8	NP_001036083.1	Q9UGN5-2
PARP2	NM_005484.4 link	c.173A>G	p.Asn58Ser	missense_variant	Exon 2 of 16		NP_005475.2	Q9UGN5-1
PARP2	XM_005267247.4 link	c.173A>G	p.Asn58Ser	missense_variant	Exon 2 of 15		XP_005267304.1
PARP2	XM_017020912.2 link	c.173A>G	p.Asn58Ser	missense_variant	Exon 2 of 15		XP_016876401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARP2	ENST00000429687.8 link	c.173A>G	p.Asn58Ser	missense_variant	Exon 2 of 16	1	NM_001042618.2	ENSP00000392972.3		Q9UGN5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249576

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135408

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

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:

0.00000137

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.173A>G (p.N58S) alteration is located in exon 2 (coding exon 2) of the PARP2 gene. This alteration results from a A to G substitution at nucleotide position 173, causing the asparagine (N) at amino acid position 58 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.74

CADD

Benign

7.1

DANN

Benign

0.77

DEOGEN2

Benign

0.020

.;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.69

T;T;T

M_CAP

Benign

0.0026

MetaRNN

Benign

0.049

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.34

N;N;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.12

N;N;N

REVEL

Benign

0.021

Sift

Benign

0.22

T;T;T

Sift4G

Benign

0.76

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.053

MutPred

0.15

Gain of phosphorylation at N58 (P = 0.0106);Gain of phosphorylation at N58 (P = 0.0106);Gain of phosphorylation at N58 (P = 0.0106);

MVP

0.33

MPC

0.079

ClinPred

0.049

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.017

gMVP

0.087

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.25

Position offset: -1

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