chr8-56441319-C-T

Variant names:

• chr8-56441319-C-T
• rs140708956
• NM_001135690.3:c.757G>A

Variant summary

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

The NM_001135690.3(PENK):​c.757G>A​(p.Glu253Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PENK NM_001135690.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.25
• 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]

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.757G>A	p.Glu253Lys	missense	Exon 4 of 4	NP_001129162.1	P01210

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PENK	ENST00000451791.7	TSL:1 MANE Select	c.757G>A	p.Glu253Lys	missense	Exon 4 of 4	ENSP00000400894.2	P01210
	PENK	ENST00000314922.3	TSL:1	c.757G>A	p.Glu253Lys	missense	Exon 2 of 2	ENSP00000324248.3	P01210
	PENK	ENST00000961478.1		c.757G>A	p.Glu253Lys	missense	Exon 4 of 4	ENSP00000631537.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	Uncertain	0.48
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.55
MutPred		0.29		Gain of ubiquitination at E253 (P = 0.0018)
MVP		0.85
MPC		0.14
ClinPred		0.90	D
GERP RS		5.9
Varity_R		0.38
gMVP		0.59
Mutation Taster		=67/33	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: rs140708956; hg19: chr8-57353878; COSMIC: COSV105123093; COSMIC: COSV105123093;