rs59191035

Positions:

• chr20-1982964-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_024411.5(PDYN):​c.121A>G​(p.Asn41Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000476 in 1,613,786 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (2 hom.)
• Consequence: PDYN NM_024411.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.482

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014978588).
• BP6: Variant 20-1982964-T-C is Benign according to our data. Variant chr20-1982964-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 447928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 357 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDYN	NM_024411.5	c.121A>G	p.Asn41Asp	missense_variant	3/4	ENST00000217305.3
PDYN-AS1	NR_134520.1	n.1252+16621T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDYN	ENST00000217305.3	c.121A>G	p.Asn41Asp	missense_variant	3/4	1	NM_024411.5	P1
PDYN-AS1	ENST00000651021.1	n.475+16621T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 357 AN: 152122 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000609 AC: 153 AN: 251422 Hom.: 1 AF XY: 0.000493 AC XY: 67 AN XY: 135880

Gnomad AFR exome AF: 0.00763

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000281 AC: 411 AN: 1461546 Hom.: 2 Cov.: 32 AF XY: 0.000290 AC XY: 211 AN XY: 727072

Gnomad4 AFR exome AF: 0.00780

Gnomad4 AMR exome AF: 0.000492

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000684

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.00234 AC: 357 AN: 152240 Hom.: 1 Cov.: 32 AF XY: 0.00235 AC XY: 175 AN XY: 74430

Gnomad4 AFR AF: 0.00773

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000910 Hom.: 0

Bravo AF: 0.00276

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00908 AC: 40

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000642 AC: 78

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 24, 2017

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2023

- -

PDYN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.088
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.55	.;T;.
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Uncertain	-0.068	T
MutationAssessor	Pathogenic	3.0	M;M;M
MutationTaster	Benign	0.72	D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.029	D;D;D
Sift4G	Uncertain	0.059	T;T;T
Polyphen		0.89	P;P;P
Vest4		0.22
MVP		0.81
MPC		0.035
ClinPred		0.069	T
GERP RS		2.5
Varity_R		0.20
gMVP		0.51

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: rs59191035; hg19: chr20-1963610;