6-163314914-G-T

Variant names:

• chr6-163314914-G-T
• rs199844557
• NM_001080379.2:c.701G>T

Variant summary

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

The NM_001080379.2(PACRG):​c.701G>T​(p.Arg234Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R234H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PACRG NM_001080379.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.58
• Publications: 6 publications found

Genes affected

PACRG (HGNC:19152): (parkin coregulated) This gene encodes a protein that is conserved across metazoans. In vertebrates, this gene is linked in a head-to-head arrangement with the adjacent parkin gene, which is associated with autosomal recessive juvenile Parkinson's disease. These genes are co-regulated in various tissues and they share a bi-directional promoter. Both genes are associated with susceptibility to leprosy. The parkin co-regulated gene protein forms a large molecular complex with chaperones, including heat shock proteins 70 and 90, and chaperonin components. This protein is also a component of Lewy bodies in Parkinson's disease patients, and it suppresses unfolded Pael receptor-induced neuronal cell death. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PACRG-AS1 (HGNC:27772): (PACRG antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080379.2. 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
	PACRG	NM_001080379.2	MANE Select	c.701G>T	p.Arg234Leu	missense	Exon 5 of 5	NP_001073848.1	Q96M98-2
	PACRG	NM_152410.3		c.818G>T	p.Arg273Leu	missense	Exon 7 of 7	NP_689623.2	Q96M98-1
	PACRG	NM_001080378.2		c.701G>T	p.Arg234Leu	missense	Exon 6 of 6	NP_001073847.1	Q96M98-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PACRG	ENST00000366888.7	TSL:1 MANE Select	c.701G>T	p.Arg234Leu	missense	Exon 5 of 5	ENSP00000355854.2	Q96M98-2
	PACRG	ENST00000366889.6	TSL:1	c.701G>T	p.Arg234Leu	missense	Exon 6 of 6	ENSP00000355855.2	Q96M98-2
	PACRG	ENST00000337019.7	TSL:2	c.818G>T	p.Arg273Leu	missense	Exon 7 of 7	ENSP00000337946.3	Q96M98-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251434 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

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	0.24
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Benign	0.88
DEOGEN2	Benign	0.36	T
Eigen	Benign	0.076
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.30
Sift	Benign	0.28	T
Sift4G	Benign	0.60	T
Polyphen		0.027	B
Vest4		0.69
MutPred		0.55		Gain of catalytic residue at R273 (P = 0.0414)
MVP		0.68
MPC		0.36
ClinPred		0.69	D
GERP RS		5.9
Varity_R		0.55
gMVP		0.71
Mutation Taster		=10/90	disease causing

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

Other links and lift over

dbSNP: rs199844557; hg19: chr6-163735946;