Variant 20-1980456-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PM5PP3_ModerateBS2

The NM_024411.5(PDYN):c.632T>C(p.Leu211Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,613,996 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L211W) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

PDYN
NM_024411.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:2U:1

Conservation

PhyloP100: 7.66

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:):

PDYN-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a peptide Big dynorphin (size 31) in uniprot entity PDYN_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_024411.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-1980456-A-C is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.901

BS2

High AC in GnomAdExome4 at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDYN	NM_024411.5 linkuse as main transcript	c.632T>C	p.Leu211Ser	missense_variant	4/4	ENST00000217305.3	NP_077722.1	P01213

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PDYN	ENST00000217305.3 linkuse as main transcript	c.632T>C	p.Leu211Ser	missense_variant	4/4	1	NM_024411.5	ENSP00000217305.2		P01213

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251434

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152112

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000557

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spinocerebellar ataxia type 23

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 12, 2010	- -
Pathogenic, no assertion criteria provided	research	O&I group, Department of Genetics, University Medical Center of Groningen	Jul 22, 2021	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 26, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;D;D

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.82

.;T;.

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.90

D;D;D

MetaSVM

Uncertain

0.45

MutationAssessor

Uncertain

2.6

M;M;M

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.6

D;D;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.84

MutPred

0.61

Gain of disorder (P = 0.0099);Gain of disorder (P = 0.0099);Gain of disorder (P = 0.0099);

MVP

0.92

MPC

0.24

ClinPred

0.94

GERP RS

5.0

Varity_R

0.54

gMVP

0.63

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