NM_024411.5:c.*1071G>A

Variant names:

• chr20-1979252-C-T
• rs752953257
• NM_024411.5:c.*1071G>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.*1071G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 152,582 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (0 hom.)
• Consequence: PDYN NM_024411.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.27
• 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 (BayesDel_noAF=-0.64).
• BP6: Variant 20-1979252-C-T is Benign according to our data. Variant chr20-1979252-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 337813.
• BS2: High AC in GnomAd4 at 187 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.*1071G>A		3_prime_UTR	Exon 4 of 4	NP_077722.1	P01213
	PDYN	NM_001190892.1		c.*1071G>A		3_prime_UTR	Exon 3 of 3	NP_001177821.1	P01213
	PDYN	NM_001190898.3		c.*1071G>A		3_prime_UTR	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.*1071G>A		3_prime_UTR	Exon 4 of 4	ENSP00000217305.2	P01213
	PDYN	ENST00000539905.5	TSL:4	c.*1071G>A		3_prime_UTR	Exon 3 of 3	ENSP00000440185.1	P01213
	PDYN	ENST00000540134.5	TSL:4	c.*1071G>A		3_prime_UTR	Exon 4 of 4	ENSP00000442259.1	P01213

Frequencies

GnomAD3 genomes AF: 0.00123 AC: 187 AN: 152178 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00462

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.000957

GnomAD4 exome AF: 0.00699 AC: 2 AN: 286 Hom.: 0 Cov.: 0 AF XY: 0.00641 AC XY: 1 AN XY: 156

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8

East Asian (EAS) AF: 0.00 AC: 0 AN: 46

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.0250 AC: 1 AN: 40

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00588 AC: 1 AN: 170

Other (OTH) AF: 0.00 AC: 0 AN: 16

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00123 AC: 187 AN: 152296 Hom.: 1 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74480

African (AFR) AF: 0.0000481 AC: 2 AN: 41560

American (AMR) AF: 0.000392 AC: 6 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00462 AC: 49 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00173 AC: 118 AN: 68020

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.000824

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.76
PhyloP100		1.3

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: rs752953257; hg19: chr20-1959898;