6-162727551-C-T

Variant names:

• chr6-162727551-C-T
• rs114231735
• NM_004562.3:c.7+111G>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.7+111G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00286 in 1,213,244 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (45 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (21 hom.)
• Consequence: PRKN NM_004562.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0760
• Publications: 0 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]

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 6-162727551-C-T is Benign according to our data. Variant chr6-162727551-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1220094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0129 (1970/152204) while in subpopulation AFR AF = 0.0444 (1845/41570). AF 95% confidence interval is 0.0427. There are 45 homozygotes in GnomAd4. There are 901 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 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.7+111G>A		intron	N/A	NP_004553.2	O60260-1
	PRKN	NM_013987.3		c.7+111G>A		intron	N/A	NP_054642.2	O60260-2
	PRKN	NM_013988.3		c.7+111G>A		intron	N/A	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.7+111G>A		intron	N/A	ENSP00000355865.1	O60260-1
	PRKN	ENST00000366897.5	TSL:1	c.7+111G>A		intron	N/A	ENSP00000355863.1	O60260-2
	PRKN	ENST00000366896.5	TSL:1	c.7+111G>A		intron	N/A	ENSP00000355862.1	O60260-6

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1968 AN: 152092 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.0444

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.00141 AC: 1499 AN: 1061040 Hom.: 21 AF XY: 0.00119 AC XY: 634 AN XY: 534920

African (AFR) AF: 0.0438 AC: 1021 AN: 23326

American (AMR) AF: 0.00381 AC: 129 AN: 33886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22076

East Asian (EAS) AF: 0.00 AC: 0 AN: 32732

South Asian (SAS) AF: 0.0000983 AC: 7 AN: 71208

European-Finnish (FIN) AF: 0.0000234 AC: 1 AN: 42796

Middle Eastern (MID) AF: 0.00537 AC: 24 AN: 4468

European-Non Finnish (NFE) AF: 0.000175 AC: 137 AN: 783882

Other (OTH) AF: 0.00386 AC: 180 AN: 46666

GnomAD4 genome AF: 0.0129 AC: 1970 AN: 152204 Hom.: 45 Cov.: 32 AF XY: 0.0121 AC XY: 901 AN XY: 74418

African (AFR) AF: 0.0444 AC: 1845 AN: 41570

American (AMR) AF: 0.00543 AC: 83 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 67982

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00979 Hom.: 2

Bravo AF: 0.0154

Asia WGS AF: 0.00607 AC: 22 AN: 3472

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	9.3
DANN	Benign	0.93
PhyloP100		-0.076
PromoterAI		-0.035	Neutral
Mutation Taster		=100/0	polymorphism

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: rs114231735; hg19: chr6-163148583;