rs45469293

Positions:

chr20-1980513-T-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_024411.5(PDYN):c.575A>T(p.Glu192Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00918 in 1,613,132 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0070 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0094 ( 86 hom. )

Consequence

PDYN
NM_024411.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.17

Variant links:

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 links:

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

PDYN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035538375).

BP6

Variant 20-1980513-T-A is Benign according to our data. Variant chr20-1980513-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 337835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-1980513-T-A is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 1068 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDYN	NM_024411.5 linkuse as main transcript	c.575A>T	p.Glu192Val	missense_variant	4/4	ENST00000217305.3	NP_077722.1
PDYN-AS1	NR_134520.1 linkuse as main transcript	n.1252+14170T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDYN	ENST00000217305.3 linkuse as main transcript	c.575A>T	p.Glu192Val	missense_variant	4/4	1	NM_024411.5	ENSP00000217305	P1
PDYN-AS1	ENST00000651021.1 linkuse as main transcript	n.475+14170T>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00703

AC:

1068

AN:

151872

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00148

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00367

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0281

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00922

Gnomad OTH

AF:

0.00433

GnomAD3 exomes

AF:

0.00825

AC:

2073

AN:

251380

Hom.:

AF XY:

0.00813

AC XY:

1105

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00309

Gnomad ASJ exome

AF:

0.00387

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.0288

Gnomad NFE exome

AF:

0.0107

Gnomad OTH exome

AF:

0.00847

GnomAD4 exome

AF:

0.00941

AC:

13748

AN:

1461142

Hom.:

Cov.:

AF XY:

0.00916

AC XY:

6660

AN XY:

726894

show subpopulations

Gnomad4 AFR exome

AF:

0.00123

Gnomad4 AMR exome

AF:

0.00300

Gnomad4 ASJ exome

AF:

0.00375

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000510

Gnomad4 FIN exome

AF:

0.0290

Gnomad4 NFE exome

AF:

0.0103

Gnomad4 OTH exome

AF:

0.00717

GnomAD4 genome

AF:

0.00703

AC:

1068

AN:

151990

Hom.:

Cov.:

AF XY:

0.00751

AC XY:

558

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.00147

Gnomad4 AMR

AF:

0.00367

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.0281

Gnomad4 NFE

AF:

0.00922

Gnomad4 OTH

AF:

0.00428

Alfa

AF:

0.00804

Hom.:

Bravo

AF:

0.00509

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.0103

AC:

ExAC

AF:

0.00857

AC:

1040

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00834

EpiControl

AF:

0.00842

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PDYN: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2023	See Variant Classification Assertion Criteria. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 20, 2019

- -

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

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

T;T;T

Eigen

Benign

-0.040

Eigen_PC

Benign

-0.043

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.54

.;T;.

MetaRNN

Benign

0.0036

T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Uncertain

2.4

M;M;M

MutationTaster

Benign

0.99

N;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.9

N;N;N

REVEL

Benign

0.21

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.076

T;T;T

Polyphen

0.70

P;P;P

Vest4

0.12

MVP

0.84

MPC

0.061

ClinPred

0.0076

GERP RS

3.8

Varity_R

0.13

gMVP

0.30

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over