NM_024411.5:c.575A>T

Variant names:

• chr20-1980513-T-A
• rs45469293
• NM_024411.5:c.575A>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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. 14/21 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.17
• Publications: 4 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 -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 Benign/Likely_benign. ClinVar VariationId is 337835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1068 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDYN	NM_024411.5	MANE Select	c.575A>T	p.Glu192Val	missense	Exon 4 of 4	NP_077722.1
	PDYN	NM_001190892.1		c.575A>T	p.Glu192Val	missense	Exon 3 of 3	NP_001177821.1
	PDYN	NM_001190898.3		c.575A>T	p.Glu192Val	missense	Exon 4 of 4	NP_001177827.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDYN	ENST00000217305.3	TSL:1 MANE Select	c.575A>T	p.Glu192Val	missense	Exon 4 of 4	ENSP00000217305.2
	PDYN	ENST00000539905.5	TSL:4	c.575A>T	p.Glu192Val	missense	Exon 3 of 3	ENSP00000440185.1
	PDYN	ENST00000540134.5	TSL:4	c.575A>T	p.Glu192Val	missense	Exon 4 of 4	ENSP00000442259.1

Frequencies

GnomAD3 genomes AF: 0.00703 AC: 1068 AN: 151872 Hom.: 6 Cov.: 32

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

GnomAD2 exomes AF: 0.00825 AC: 2073 AN: 251380 AF XY: 0.00813

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 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.: 86 Cov.: 32 AF XY: 0.00916 AC XY: 6660 AN XY: 726894

African (AFR) AF: 0.00123 AC: 41 AN: 33408

American (AMR) AF: 0.00300 AC: 134 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 98 AN: 26120

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

South Asian (SAS) AF: 0.000510 AC: 44 AN: 86244

European-Finnish (FIN) AF: 0.0290 AC: 1551 AN: 53416

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5760

European-Non Finnish (NFE) AF: 0.0103 AC: 11444 AN: 1111488

Other (OTH) AF: 0.00717 AC: 433 AN: 60356

GnomAD4 genome AF: 0.00703 AC: 1068 AN: 151990 Hom.: 6 Cov.: 32 AF XY: 0.00751 AC XY: 558 AN XY: 74286

African (AFR) AF: 0.00147 AC: 61 AN: 41450

American (AMR) AF: 0.00367 AC: 56 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5148

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4808

European-Finnish (FIN) AF: 0.0281 AC: 297 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00922 AC: 627 AN: 67970

Other (OTH) AF: 0.00428 AC: 9 AN: 2102

Alfa AF: 0.00804 Hom.: 9

Bravo AF: 0.00509

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0103 AC: 89

ExAC AF: 0.00857 AC: 1040

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00834

EpiControl AF: 0.00842

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	1	not specified (1)
-	-	1	Spinocerebellar ataxia type 23 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.040
Eigen_PC	Benign	-0.043
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.2
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.21
Sift	Benign	0.11	T
Sift4G	Benign	0.076	T
Polyphen		0.70	P
Vest4		0.12
MVP		0.84
MPC		0.061
ClinPred		0.0076	T
GERP RS		3.8
Varity_R		0.13
gMVP		0.30
Mutation Taster		=100/0	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: rs45469293; hg19: chr20-1961159;