8-56441576-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001135690.3(PENK):c.500G>A(p.Arg167Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: PENK NM_001135690.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.196

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07903406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PENK	NM_001135690.3	c.500G>A	p.Arg167Gln	missense_variant	4/4	ENST00000451791.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PENK	ENST00000451791.7	c.500G>A	p.Arg167Gln	missense_variant	4/4	1	NM_001135690.3	P1
PENK	ENST00000314922.3	c.500G>A	p.Arg167Gln	missense_variant	2/2	1		P1
PENK	ENST00000517415.1	c.129+4240G>A		intron_variant		3
PENK	ENST00000523274.1	n.422G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251448 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461768 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

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

Mar 02, 2023

The c.500G>A (p.R167Q) 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 500, causing the arginine (R) at amino acid position 167 to be replaced by a glutamine (Q). 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	0.066
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	3.8
Dann	Benign	0.97
DEOGEN2	Benign	0.087	T;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.12	N
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.079	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.070	N;N
REVEL	Benign	0.046
Sift	Benign	0.43	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.88	P;P
Vest4		0.049
MutPred		0.21		Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);
MVP		0.34
MPC		0.038
ClinPred		0.073	T
GERP RS		0.67
Varity_R		0.043
gMVP		0.20

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: rs1298980473; hg19: chr8-57354135; COSMIC: COSV59241411; COSMIC: COSV59241411;