14-20354149-A-G

Position:

• chr14-20354149-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000429687.8(PARP2):​c.665A>G​(p.Asp222Gly) variant causes a missense change. The variant allele was found at a frequency of 0.02 in 1,612,584 control chromosomes in the GnomAD database, including 470 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (49 hom., cov: 32)
  • Exomes 𝑓: 0.020 (421 hom.)
• Consequence: PARP2 ENST00000429687.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.06

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003672868).
• BP6: Variant 14-20354149-A-G is Benign according to our data. Variant chr14-20354149-A-G is described in ClinVar as [Benign]. Clinvar id is 1230992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0186 (2835/152294) while in subpopulation NFE AF= 0.0244 (1659/68026). AF 95% confidence interval is 0.0234. There are 49 homozygotes in gnomad4. There are 1519 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PARP2	NM_001042618.2	c.665A>G	p.Asp222Gly	missense_variant	8/16	ENST00000429687.8	NP_001036083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PARP2	ENST00000429687.8	c.665A>G	p.Asp222Gly	missense_variant	8/16	1	NM_001042618.2	ENSP00000392972	P2

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2835 AN: 152176 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0726

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0244

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0193 AC: 4817 AN: 249530 Hom.: 98 AF XY: 0.0190 AC XY: 2575 AN XY: 135380

Gnomad AFR exome AF: 0.00284

Gnomad AMR exome AF: 0.00704

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000980

Gnomad FIN exome AF: 0.0675

Gnomad NFE exome AF: 0.0242

Gnomad OTH exome AF: 0.0195

GnomAD4 exome AF: 0.0201 AC: 29389 AN: 1460290 Hom.: 421 Cov.: 29 AF XY: 0.0195 AC XY: 14203 AN XY: 726558

Gnomad4 AFR exome AF: 0.00290

Gnomad4 AMR exome AF: 0.00686

Gnomad4 ASJ exome AF: 0.0160

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000905

Gnomad4 FIN exome AF: 0.0662

Gnomad4 NFE exome AF: 0.0215

Gnomad4 OTH exome AF: 0.0175

GnomAD4 genome AF: 0.0186 AC: 2835 AN: 152294 Hom.: 49 Cov.: 32 AF XY: 0.0204 AC XY: 1519 AN XY: 74462

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0726

Gnomad4 NFE AF: 0.0244

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.0196 Hom.: 93

Bravo AF: 0.0133

TwinsUK AF: 0.0156 AC: 58

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00243 AC: 9

ESP6500EA AF: 0.0230 AC: 189

ExAC AF: 0.0194 AC: 2342

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0195

EpiControl AF: 0.0168

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	PARP2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 2019	This variant is associated with the following publications: (PMID: 29484706) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	.;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D;D
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.3	.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Benign	0.17
Sift	Benign	0.032	D;D;D
Sift4G	Benign	0.098	T;T;T
Polyphen		0.36	B;P;.
Vest4		0.18
MPC		0.38
ClinPred		0.066	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.51

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

Other links and lift over

dbSNP: rs3093921; hg19: chr14-20822308; COSMIC: COSV51637877; COSMIC: COSV51637877;