chr8-56441674-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001135690.3(PENK):ā€‹c.402G>Cā€‹(p.Lys134Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000026 ( 0 hom., cov: 32)
Exomes š‘“: 0.000025 ( 0 hom. )

Consequence

PENK
NM_001135690.3 missense

Scores

3
9
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.774
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.771

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PENKNM_001135690.3 linkuse as main transcriptc.402G>C p.Lys134Asn missense_variant 4/4 ENST00000451791.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PENKENST00000451791.7 linkuse as main transcriptc.402G>C p.Lys134Asn missense_variant 4/41 NM_001135690.3 P1
PENKENST00000314922.3 linkuse as main transcriptc.402G>C p.Lys134Asn missense_variant 2/21 P1
PENKENST00000517415.1 linkuse as main transcriptc.129+4142G>C intron_variant 3
PENKENST00000523274.1 linkuse as main transcriptn.324G>C non_coding_transcript_exon_variant 2/22

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
151882
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000442
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000477
AC:
12
AN:
251492
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135922
show subpopulations
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000105
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000253
AC:
37
AN:
1461852
Hom.:
0
Cov.:
33
AF XY:
0.0000248
AC XY:
18
AN XY:
727230
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000333
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
151882
Hom.:
0
Cov.:
32
AF XY:
0.0000270
AC XY:
2
AN XY:
74194
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000442
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000450
Hom.:
0
Bravo
AF:
0.0000264
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 16, 2024The c.402G>C (p.K134N) alteration is located in exon 2 (coding exon 2) of the PENK gene. This alteration results from a G to C substitution at nucleotide position 402, causing the lysine (K) at amino acid position 134 to be replaced by an asparagine (N). 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
Pathogenic
0.94
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.42
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.76
D;D
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.91
.;D
M_CAP
Benign
0.019
T
MetaRNN
Pathogenic
0.77
D;D
MetaSVM
Benign
-0.96
T
MutationAssessor
Pathogenic
3.3
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.53
T
PROVEAN
Uncertain
-3.5
D;D
REVEL
Benign
0.24
Sift
Benign
0.075
T;T
Sift4G
Uncertain
0.051
T;T
Polyphen
1.0
D;D
Vest4
0.77
MutPred
0.36
Loss of ubiquitination at K134 (P = 0.0034);Loss of ubiquitination at K134 (P = 0.0034);
MVP
0.59
MPC
0.21
ClinPred
0.80
D
GERP RS
4.2
Varity_R
0.38
gMVP
0.60

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs374580134; hg19: chr8-57354233; API