chr8-56445881-C-T

Position:

• chr8-56445881-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 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

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PENK	NM_001135690.3	c.73G>A	p.Glu25Lys	missense_variant	3/4	ENST00000451791.7
PENK-AS1	NR_125813.1	n.75C>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PENK	ENST00000451791.7	c.73G>A	p.Glu25Lys	missense_variant	3/4	1	NM_001135690.3	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.73G>A (p.E25K) alteration is located in exon 1 (coding exon 1) of the PENK gene. This alteration results from a G to A substitution at nucleotide position 73, causing the glutamic acid (E) at amino acid position 25 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;D;T;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.85	T;.;D;D;T;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.6	.;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.010	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;.;D;D
Polyphen		0.99, 1.0	.;D;D;.;.;D
Vest4		0.34, 0.52, 0.57, 0.31
MutPred		0.61		.;Gain of methylation at E25 (P = 0.01);Gain of methylation at E25 (P = 0.01);Gain of methylation at E25 (P = 0.01);Gain of methylation at E25 (P = 0.01);Gain of methylation at E25 (P = 0.01);
MVP		0.84
MPC		1.8
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.33
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-57358440; COSMIC: COSV59241339; COSMIC: COSV59241339;