chr20-1980820-C-T

Variant names:

• chr20-1980820-C-T
• rs201585283
• NM_024411.5:c.268G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_024411.5(PDYN):​c.268G>A​(p.Gly90Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,614,098 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: PDYN NM_024411.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.41
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007458687).
• BP6: Variant 20-1980820-C-T is Benign according to our data. Variant chr20-1980820-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 447929.
• BS2: High AC in GnomAd4 at 23 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024411.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDYN	NM_024411.5	MANE Select	c.268G>A	p.Gly90Arg	missense	Exon 4 of 4	NP_077722.1	P01213
	PDYN	NM_001190892.1		c.268G>A	p.Gly90Arg	missense	Exon 3 of 3	NP_001177821.1	P01213
	PDYN	NM_001190898.3		c.268G>A	p.Gly90Arg	missense	Exon 4 of 4	NP_001177827.1	P01213

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDYN	ENST00000217305.3	TSL:1 MANE Select	c.268G>A	p.Gly90Arg	missense	Exon 4 of 4	ENSP00000217305.2	P01213
	PDYN	ENST00000539905.5	TSL:4	c.268G>A	p.Gly90Arg	missense	Exon 3 of 3	ENSP00000440185.1	P01213
	PDYN	ENST00000540134.5	TSL:4	c.268G>A	p.Gly90Arg	missense	Exon 4 of 4	ENSP00000442259.1	P01213

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000219 AC: 55 AN: 251402 AF XY: 0.000206

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000133 AC: 194 AN: 1461894 Hom.: 1 Cov.: 32 AF XY: 0.000147 AC XY: 107 AN XY: 727248

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00494 AC: 129 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1112012

Other (OTH) AF: 0.000546 AC: 33 AN: 60396

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000442 Hom.: 0

Bravo AF: 0.000151

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.4
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.66	N
REVEL	Benign	0.16
Sift	Benign	0.32	T
Sift4G	Benign	0.48	T
Polyphen		0.22	B
Vest4		0.10
MutPred		0.26		Gain of solvent accessibility (P = 0.0471)
MVP		0.81
MPC		0.033
ClinPred		0.058	T
GERP RS		4.7
Varity_R		0.085
gMVP		0.14
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs201585283; hg19: chr20-1961466;