20-1994400-AAGAGAGAGAG-AAGAGAGAG

Variant names:

• chr20-1994400-AAG-A
• rs34535593
• ENST00000446562.1:n.1217-12531_1217-12530delAG

Variant summary

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

The ENST00000446562.1(PDYN-AS1):​n.1217-12531_1217-12530delAG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 150,010 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000093 (0 hom., cov: 30)
  • Exomes 𝑓: 0.071 (0 hom.)
• Consequence: PDYN-AS1 ENST00000446562.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.741
• Publications: 2 publications found

Genes affected

PDYN-AS1 (HGNC:53462): (PDYN antisense RNA 1)

PDYN (HGNC:8820): (prodynorphin) The protein encoded by this gene is a preproprotein that is proteolytically processed to form the secreted opioid peptides beta-neoendorphin, dynorphin, leu-enkephalin, rimorphin, and leumorphin. These peptides are ligands for the kappa-type of opioid receptor. Dynorphin is involved in modulating responses to several psychoactive substances, including cocaine. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2010]

PDYN Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 23

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000446562.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDYN-AS1	NR_134520.1		n.1253-12514_1253-12513delGA		intron	N/A
	PDYN	NM_001190899.2		c.-511_-510delCT		upstream_gene	N/A	NP_001177828.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDYN-AS1	ENST00000446562.1	TSL:2	n.1217-12531_1217-12530delAG		intron	N/A
	PDYN-AS1	ENST00000651021.1		n.475+28058_475+28059delAG		intron	N/A
	PDYN	ENST00000539905.5	TSL:4	c.-511_-510delCT		upstream_gene	N/A	ENSP00000440185.1

Frequencies

GnomAD3 genomes AF: 0.0000935 AC: 14 AN: 149774 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000663

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000301

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000134

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0714 AC: 10 AN: 140 Hom.: 0 AF XY: 0.0625 AC XY: 6 AN XY: 96

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.250 AC: 1 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.0333 AC: 1 AN: 30

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.0952 AC: 8 AN: 84

Other (OTH) AF: 0.00 AC: 0 AN: 12

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000934 AC: 14 AN: 149870 Hom.: 0 Cov.: 30 AF XY: 0.0000957 AC XY: 7 AN XY: 73140

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000243 AC: 1 AN: 41090

American (AMR) AF: 0.0000662 AC: 1 AN: 15096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3432

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4730

European-Finnish (FIN) AF: 0.000301 AC: 3 AN: 9966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000134 AC: 9 AN: 67142

Other (OTH) AF: 0.00 AC: 0 AN: 2076

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.74
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs34535593; hg19: chr20-1975046;