10-49861626-C-T

Variant names:

• chr10-49861626-C-T
• rs376720259
• NM_003631.5:c.2167G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003631.5(PARG):​c.2167G>A​(p.Glu723Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,574,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: PARG NM_003631.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51
• Publications: 1 publications found

Genes affected

PARG (HGNC:8605): (poly(ADP-ribose) glycohydrolase) Poly(ADP-ribose) glycohydrolase (PARG) is the major enzyme responsible for the catabolism of poly(ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14620042).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003631.5. 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
	PARG	NM_003631.5	MANE Select	c.2167G>A	p.Glu723Lys	missense	Exon 12 of 18	NP_003622.2	Q86W56-1
	PARG	NM_001303486.3		c.1921G>A	p.Glu641Lys	missense	Exon 12 of 18	NP_001290415.1	Q86W56-2
	PARG	NM_001324381.3		c.1921G>A	p.Glu641Lys	missense	Exon 12 of 18	NP_001311310.1	Q86W56-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARG	ENST00000616448.2	TSL:1 MANE Select	c.2167G>A	p.Glu723Lys	missense	Exon 12 of 18	ENSP00000484285.1	Q86W56-1
	PARG	ENST00000402038.7	TSL:1	c.2167G>A	p.Glu723Lys	missense	Exon 13 of 19	ENSP00000384408.3	Q86W56-1
	PARG	ENST00000941174.1		c.2167G>A	p.Glu723Lys	missense	Exon 12 of 18	ENSP00000611233.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151884 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000326 AC: 4 AN: 122612 AF XY: 0.0000306

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000119

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000190 AC: 27 AN: 1422778 Hom.: 0 Cov.: 25 AF XY: 0.0000198 AC XY: 14 AN XY: 707692

African (AFR) AF: 0.0000306 AC: 1 AN: 32730

American (AMR) AF: 0.00 AC: 0 AN: 43054

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25718

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39148

South Asian (SAS) AF: 0.0000484 AC: 4 AN: 82644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4066

European-Non Finnish (NFE) AF: 0.0000185 AC: 20 AN: 1083834

Other (OTH) AF: 0.0000170 AC: 1 AN: 58884

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152002 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 74314

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67962

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.0000540 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000316 AC: 1

ExAC AF: 0.0000418 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	0.0089	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.090
Eigen_PC	Benign	0.061
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.2	L
PhyloP100		2.5
PrimateAI	Pathogenic	0.82	D
REVEL	Benign	0.092
Sift4G	Benign	0.32	T
Polyphen		0.64	P
Vest4		0.39
MVP		0.30
ClinPred		0.25	T
GERP RS		4.8
Varity_R		0.45
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs376720259; hg19: chr10-51069672;