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GeneBe

8-56441347-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_001135690.3(PENK):c.729C>T(p.Ser243=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00576 in 1,613,738 control chromosomes in the GnomAD database, including 447 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.030 ( 234 hom., cov: 32)
Exomes 𝑓: 0.0032 ( 213 hom. )

Consequence

PENK
NM_001135690.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.609
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 8-56441347-G-A is Benign according to our data. Variant chr8-56441347-G-A is described in ClinVar as [Benign]. Clinvar id is 780756.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.609 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PENKNM_001135690.3 linkuse as main transcriptc.729C>T p.Ser243= synonymous_variant 4/4 ENST00000451791.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PENKENST00000451791.7 linkuse as main transcriptc.729C>T p.Ser243= synonymous_variant 4/41 NM_001135690.3 P1
PENKENST00000314922.3 linkuse as main transcriptc.729C>T p.Ser243= synonymous_variant 2/21 P1
PENKENST00000517415.1 linkuse as main transcriptc.130-4271C>T intron_variant 3
PENKENST00000523274.1 linkuse as main transcript downstream_gene_variant 2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0299
AC:
4554
AN:
152126
Hom.:
232
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.104
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0114
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00124
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000338
Gnomad OTH
AF:
0.0220
GnomAD3 exomes
AF:
0.00794
AC:
1994
AN:
251156
Hom.:
93
AF XY:
0.00571
AC XY:
775
AN XY:
135766
show subpopulations
Gnomad AFR exome
AF:
0.109
Gnomad AMR exome
AF:
0.00528
Gnomad ASJ exome
AF:
0.000298
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000261
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000141
Gnomad OTH exome
AF:
0.00326
GnomAD4 exome
AF:
0.00324
AC:
4729
AN:
1461494
Hom.:
213
Cov.:
32
AF XY:
0.00276
AC XY:
2005
AN XY:
727076
show subpopulations
Gnomad4 AFR exome
AF:
0.113
Gnomad4 AMR exome
AF:
0.00574
Gnomad4 ASJ exome
AF:
0.000421
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.000336
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000142
Gnomad4 OTH exome
AF:
0.00714
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0300
AC:
4570
AN:
152244
Hom.:
234
Cov.:
32
AF XY:
0.0295
AC XY:
2196
AN XY:
74432
show subpopulations
Gnomad4 AFR
AF:
0.104
Gnomad4 AMR
AF:
0.0114
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00104
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000338
Gnomad4 OTH
AF:
0.0218
Alfa
AF:
0.0134
Hom.:
47
Bravo
AF:
0.0349
Asia WGS
AF:
0.00577
AC:
20
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.000119

ClinVar

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

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJul 23, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.82
Cadd
Benign
0.33
Dann
Benign
0.87

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: rs35794206; hg19: chr8-57353906; COSMIC: COSV105123088; COSMIC: COSV105123088; API