20-1979667-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024411.5(PDYN):c.*656T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 157,242 control chromosomes in the GnomAD database, including 1,196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1176 hom., cov: 31)
  • Exomes 𝑓: 0.081 (20 hom.)
• Consequence: PDYN NM_024411.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.664

Genes affected

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

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 20-1979667-A-G is Benign according to our data. Variant chr20-1979667-A-G is described in ClinVar as [Benign]. Clinvar id is 337822.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDYN	NM_024411.5	c.*656T>C		3_prime_UTR_variant	4/4	ENST00000217305.3
PDYN-AS1	NR_134520.1	n.1252+13324A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDYN	ENST00000217305.3	c.*656T>C		3_prime_UTR_variant	4/4	1	NM_024411.5	P1
PDYN-AS1	ENST00000651021.1	n.475+13324A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18036 AN: 152032 Hom.: 1174 Cov.: 31

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0598

Gnomad FIN AF: 0.0813

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.139

GnomAD4 exome AF: 0.0805 AC: 410 AN: 5092 Hom.: 20 Cov.: 0 AF XY: 0.0805 AC XY: 216 AN XY: 2684

Gnomad4 AFR exome AF: 0.188

Gnomad4 AMR exome AF: 0.0619

Gnomad4 ASJ exome AF: 0.214

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0389

Gnomad4 FIN exome AF: 0.143

Gnomad4 NFE exome AF: 0.0989

Gnomad4 OTH exome AF: 0.0875

GnomAD4 genome AF: 0.119 AC: 18057 AN: 152150 Hom.: 1176 Cov.: 31 AF XY: 0.115 AC XY: 8582 AN XY: 74398

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.0998

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.0609

Gnomad4 FIN AF: 0.0813

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.138

Alfa AF: 0.120 Hom.: 888

Bravo AF: 0.124

Asia WGS AF: 0.0390 AC: 136 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spinocerebellar ataxia type 23 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	4.2
Dann	Benign	0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs10485703; hg19: chr20-1960313;