8-56445881-C-T

Variant names:

• chr8-56445881-C-T
• rs1034925038
• NM_001135690.3:c.73G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001135690.3(PENK):​c.73G>A​(p.Glu25Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E25A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PENK NM_001135690.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.22
• Publications: 0 publications found

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]

PENK-AS1 (HGNC:55519): (PENK antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135690.3. 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
	PENK	NM_001135690.3	MANE Select	c.73G>A	p.Glu25Lys	missense	Exon 3 of 4	NP_001129162.1	P01210
	PENK-AS1	NR_125813.1		n.75C>T		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PENK	ENST00000451791.7	TSL:1 MANE Select	c.73G>A	p.Glu25Lys	missense	Exon 3 of 4	ENSP00000400894.2	P01210
	PENK	ENST00000314922.3	TSL:1	c.73G>A	p.Glu25Lys	missense	Exon 1 of 2	ENSP00000324248.3	P01210
	PENK	ENST00000961478.1		c.73G>A	p.Glu25Lys	missense	Exon 3 of 4	ENSP00000631537.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.34
MutPred		0.61		Gain of methylation at E25 (P = 0.01)
MVP		0.84
MPC		1.8
ClinPred		0.99	D
GERP RS		5.3
PromoterAI		-0.0032	Neutral
Varity_R		0.33
gMVP		0.53
Mutation Taster		=82/18	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: rs1034925038; hg19: chr8-57358440; COSMIC: COSV59241339; COSMIC: COSV59241339;