rs267606939

chr20-1980445-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP3_ModeratePP5

The NM_024411.5(PDYN):c.643C>T(p.Arg215Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,614,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R215H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PDYN
NM_024411.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.45

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 Uncertain_significance. Variant got 5 ACMG points.

PM1

In a peptide Dynorphin A(1-13) (size 12) in uniprot entity PDYN_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_024411.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

PP5

Variant 20-1980445-G-A is Pathogenic according to our data. Variant chr20-1980445-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 18459.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr20-1980445-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PDYN	NM_024411.5 linkuse as main transcript	c.643C>T	p.Arg215Cys	missense_variant	4/4	ENST00000217305.3
PDYN-AS1	NR_134520.1 linkuse as main transcript	n.1252+14102G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PDYN	ENST00000217305.3 linkuse as main transcript	c.643C>T	p.Arg215Cys	missense_variant	4/4	1	NM_024411.5	P1
PDYN-AS1	ENST00000651021.1 linkuse as main transcript	n.475+14102G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251430

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Spinocerebellar ataxia type 23

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 12, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.39

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

D;D;D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.96

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Uncertain

0.75

MutationAssessor

Pathogenic

3.3

M;M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-7.0

D;D;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.90

MVP

0.96

MPC

0.24

ClinPred

1.0

GERP RS

5.0

Varity_R

0.72

gMVP

0.57

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