rs2576573

Positions:

• chr8-56445416-G-A
• chr8-56445416-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001135690.3(PENK):​c.138+400C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 443,382 control chromosomes in the GnomAD database, including 41,561 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.39 (12078 hom., cov: 32)
  • Exomes 𝑓: 0.44 (29483 hom.)
• Consequence: PENK NM_001135690.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.515

Genes affected

PENK (HGNC:8831): (proenkephalin) This gene encodes a preproprotein that is proteolytically processed to generate multiple protein products. These products include the pentapeptide opioids Met-enkephalin and Leu-enkephalin, which are stored in synaptic vesicles, then released into the synapse where they bind to mu- and delta-opioid receptors to modulate the perception of pain. Other non-opioid cleavage products may function in distinct biological activities. [provided by RefSeq, Jul 2015]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PENK	NM_001135690.3	c.138+400C>T		intron_variant		ENST00000451791.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PENK	ENST00000451791.7	c.138+400C>T		intron_variant		1	NM_001135690.3	P1

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58579 AN: 151912 Hom.: 12070 Cov.: 32

Gnomad AFR AF: 0.241

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.356

Gnomad ASJ AF: 0.492

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.535

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.392

GnomAD4 exome AF: 0.444 AC: 129274 AN: 291352 Hom.: 29483 Cov.: 0 AF XY: 0.446 AC XY: 66362 AN XY: 148778

Gnomad4 AFR exome AF: 0.255

Gnomad4 AMR exome AF: 0.378

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.353

Gnomad4 SAS exome AF: 0.502

Gnomad4 FIN exome AF: 0.522

Gnomad4 NFE exome AF: 0.455

Gnomad4 OTH exome AF: 0.436

GnomAD4 genome AF: 0.386 AC: 58608 AN: 152030 Hom.: 12078 Cov.: 32 AF XY: 0.388 AC XY: 28866 AN XY: 74304

Gnomad4 AFR AF: 0.241

Gnomad4 AMR AF: 0.356

Gnomad4 ASJ AF: 0.492

Gnomad4 EAS AF: 0.353

Gnomad4 SAS AF: 0.472

Gnomad4 FIN AF: 0.535

Gnomad4 NFE AF: 0.447

Gnomad4 OTH AF: 0.391

Alfa AF: 0.425 Hom.: 3352

Bravo AF: 0.366

Asia WGS AF: 0.413 AC: 1439 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.0
DANN	Benign	0.69

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

Other links and lift over

dbSNP: rs2576573; hg19: chr8-57357975;