NM_004562.3:c.1180G>A

Variant names:

• chr6-161360193-C-T
• rs1801334
• NM_004562.3:c.1180G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004562.3(PRKN):​c.1180G>A​(p.Asp394Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0341 in 1,613,134 control chromosomes in the GnomAD database, including 1,150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D394G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.025 (64 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1086 hom.)
• Consequence: PRKN NM_004562.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.29
• Publications: 44 publications found

Genes affected

PRKN (HGNC:8607): (parkin RBR E3 ubiquitin protein ligase) The precise function of this gene is unknown; however, the encoded protein is a component of a multiprotein E3 ubiquitin ligase complex that mediates the targeting of substrate proteins for proteasomal degradation. Mutations in this gene are known to cause Parkinson disease and autosomal recessive juvenile Parkinson disease. Alternative splicing of this gene produces multiple transcript variants encoding distinct isoforms. Additional splice variants of this gene have been described but currently lack transcript support. [provided by RefSeq, Jul 2008]

PRKN Gene-Disease associations (from GenCC):

• autosomal recessive juvenile Parkinson disease 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
• Parkinson disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• young-onset Parkinson disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038829148).
• BP6: Variant 6-161360193-C-T is Benign according to our data. Variant chr6-161360193-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 41222.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 = 0.025 (3807/152308) while in subpopulation NFE AF = 0.0378 (2571/68026). AF 95% confidence interval is 0.0366. There are 64 homozygotes in GnomAd4. There are 1837 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 64 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004562.3. 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
	PRKN	NM_004562.3	MANE Select	c.1180G>A	p.Asp394Asn	missense	Exon 11 of 12	NP_004553.2	O60260-1
	PRKN	NM_013987.3		c.1096G>A	p.Asp366Asn	missense	Exon 10 of 11	NP_054642.2	O60260-2
	PRKN	NM_013988.3		c.733G>A	p.Asp245Asn	missense	Exon 8 of 9	NP_054643.2	O60260-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRKN	ENST00000366898.6	TSL:1 MANE Select	c.1180G>A	p.Asp394Asn	missense	Exon 11 of 12	ENSP00000355865.1	O60260-1
	PRKN	ENST00000366897.5	TSL:1	c.1096G>A	p.Asp366Asn	missense	Exon 10 of 11	ENSP00000355863.1	O60260-2
	PRKN	ENST00000366896.5	TSL:1	c.733G>A	p.Asp245Asn	missense	Exon 8 of 9	ENSP00000355862.1	O60260-6

Frequencies

GnomAD3 genomes AF: 0.0250 AC: 3810 AN: 152190 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.00914

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.0507

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0334

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0378

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0255 AC: 6405 AN: 251482 AF XY: 0.0255

Gnomad AFR exome AF: 0.00763

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.0383

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0336

Gnomad NFE exome AF: 0.0391

Gnomad OTH exome AF: 0.0264

GnomAD4 exome AF: 0.0350 AC: 51172 AN: 1460826 Hom.: 1086 Cov.: 31 AF XY: 0.0341 AC XY: 24749 AN XY: 726818

African (AFR) AF: 0.00827 AC: 277 AN: 33476

American (AMR) AF: 0.0126 AC: 564 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0388 AC: 1015 AN: 26128

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00371 AC: 320 AN: 86242

European-Finnish (FIN) AF: 0.0334 AC: 1782 AN: 53410

Middle Eastern (MID) AF: 0.00920 AC: 53 AN: 5764

European-Non Finnish (NFE) AF: 0.0408 AC: 45279 AN: 1111022

Other (OTH) AF: 0.0311 AC: 1879 AN: 60360

GnomAD4 genome AF: 0.0250 AC: 3807 AN: 152308 Hom.: 64 Cov.: 32 AF XY: 0.0247 AC XY: 1837 AN XY: 74480

African (AFR) AF: 0.00912 AC: 379 AN: 41566

American (AMR) AF: 0.0142 AC: 217 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0507 AC: 176 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00331 AC: 16 AN: 4828

European-Finnish (FIN) AF: 0.0334 AC: 355 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0378 AC: 2571 AN: 68026

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.0337 Hom.: 264

Bravo AF: 0.0239

TwinsUK AF: 0.0375 AC: 139

ALSPAC AF: 0.0353 AC: 136

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0443 AC: 381

ExAC AF: 0.0256 AC: 3108

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0381

EpiControl AF: 0.0372

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Autosomal recessive juvenile Parkinson disease 2 (2)
-	-	1	Lung cancer;C0919267:Ovarian neoplasm;C1868675:Autosomal recessive juvenile Parkinson disease 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0039	T
MetaSVM	Uncertain	0.0043	D
PhyloP100		4.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.023	D
Sift4G	Benign	0.071	T
Polyphen		0.56	P
Vest4		0.27
MPC		0.063
ClinPred		0.044	T
GERP RS		4.0
Varity_R		0.40
gMVP		0.71
Mutation Taster		=88/12	polymorphism (auto)

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: rs1801334; hg19: chr6-161781225; COSMIC: COSV58225382;