8-56441319-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 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 rank	MANE	Protein	UniProt
PENK	NM_001135690.3	c.757G>A	p.Glu253Lys	missense_variant	Exon 4 of 4	ENST00000451791.7	NP_001129162.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PENK	ENST00000451791.7	c.757G>A	p.Glu253Lys	missense_variant	Exon 4 of 4	1	NM_001135690.3	ENSP00000400894.2
PENK	ENST00000314922.3	c.757G>A	p.Glu253Lys	missense_variant	Exon 2 of 2	1		ENSP00000324248.3
PENK	ENST00000517415.1	c.130-4243G>A		intron_variant	Intron 1 of 1	3		ENSP00000430268.1
PENK	ENST00000523274.1	n.*73G>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.757G>A (p.E253K) alteration is located in exon 2 (coding exon 2) of the PENK gene. This alteration results from a G to A substitution at nucleotide position 757, causing the glutamic acid (E) at amino acid position 253 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	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;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;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.99	D;D
Vest4		0.55
MutPred		0.29		Gain of ubiquitination at E253 (P = 0.0018);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

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: rs140708956; hg19: chr8-57353878; COSMIC: COSV105123093; COSMIC: COSV105123093;