rs77155664

Variant names:

• chr20-1980652-T-G
• rs77155664
• NM_024411.5:c.436A>C

Your query was ambiguous. Multiple possible variants found:

• chr20-1980652-T-G
• chr20-1980652-T-A

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.436A>C​(p.Met146Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00673 in 1,614,150 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M146K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0051 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (61 hom.)
• Consequence: PDYN NM_024411.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.41
• Publications: 9 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=0.0040592253).
• BP6: Variant 20-1980652-T-G is Benign according to our data. Variant chr20-1980652-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 337839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 776 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.436A>C	p.Met146Leu	missense	Exon 4 of 4	NP_077722.1	P01213
	PDYN	NM_001190892.1		c.436A>C	p.Met146Leu	missense	Exon 3 of 3	NP_001177821.1	P01213
	PDYN	NM_001190898.3		c.436A>C	p.Met146Leu	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.436A>C	p.Met146Leu	missense	Exon 4 of 4	ENSP00000217305.2	P01213
	PDYN	ENST00000539905.5	TSL:4	c.436A>C	p.Met146Leu	missense	Exon 3 of 3	ENSP00000440185.1	P01213
	PDYN	ENST00000540134.5	TSL:4	c.436A>C	p.Met146Leu	missense	Exon 4 of 4	ENSP00000442259.1	P01213

Frequencies

GnomAD3 genomes AF: 0.00510 AC: 776 AN: 152162 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0130

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00788

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00492 AC: 1236 AN: 251432 AF XY: 0.00472

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.00745

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00690 AC: 10088 AN: 1461870 Hom.: 61 Cov.: 32 AF XY: 0.00669 AC XY: 4867 AN XY: 727236

African (AFR) AF: 0.000836 AC: 28 AN: 33480

American (AMR) AF: 0.00150 AC: 67 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26136

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

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86258

European-Finnish (FIN) AF: 0.0127 AC: 677 AN: 53420

Middle Eastern (MID) AF: 0.00329 AC: 19 AN: 5768

European-Non Finnish (NFE) AF: 0.00805 AC: 8948 AN: 1111988

Other (OTH) AF: 0.00498 AC: 301 AN: 60396

GnomAD4 genome AF: 0.00510 AC: 776 AN: 152280 Hom.: 3 Cov.: 32 AF XY: 0.00526 AC XY: 392 AN XY: 74458

African (AFR) AF: 0.00101 AC: 42 AN: 41564

American (AMR) AF: 0.00366 AC: 56 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

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

European-Finnish (FIN) AF: 0.0130 AC: 138 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00788 AC: 536 AN: 68016

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00517 Hom.: 6

Bravo AF: 0.00399

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00744 AC: 64

ExAC AF: 0.00463 AC: 562

EpiCase AF: 0.00714

EpiControl AF: 0.00670

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Spinocerebellar ataxia type 23 (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.0020
DANN	Benign	0.69
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.86	L
PhyloP100		-2.4
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.12
Sift	Benign	0.39	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.32		Loss of catalytic residue at M146 (P = 0.0268)
MVP		0.38
MPC		0.026
ClinPred		0.0027	T
GERP RS		-9.4
Varity_R		0.044
gMVP		0.15
Mutation Taster		=98/2	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: rs77155664; hg19: chr20-1961298;