Genetic Variant PENK:c.-3-167C>G (chr8-56446123-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001135690.3(PENK):c.-3-167C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 732,162 control chromosomes in the GnomAD database, including 232,902 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.83 ( 52190 hom., cov: 33)

Exomes 𝑓: 0.79 ( 180712 hom. )

Consequence

PENK
NM_001135690.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.223

Publications

6 publications found

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]

PENK links:

PENK-AS1 (HGNC:55519): (PENK antisense RNA 1)

PENK-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PENK	NM_001135690.3 link	c.-3-167C>G		intron_variant	Intron 2 of 3	ENST00000451791.7	NP_001129162.1	P01210A0A024R7V4
PENK-AS1	NR_125813.1 link	n.317G>C		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PENK	ENST00000451791.7 link	c.-3-167C>G		intron_variant	Intron 2 of 3	1	NM_001135690.3	ENSP00000400894.2		P01210

Frequencies

GnomAD3 genomes

AF:

0.825

AC:

125427

AN:

152048

Hom.:

52134

Cov.:

show subpopulations

Gnomad AFR

AF:

0.928

Gnomad AMI

AF:

0.806

Gnomad AMR

AF:

0.826

Gnomad ASJ

AF:

0.797

Gnomad EAS

AF:

0.870

Gnomad SAS

AF:

0.847

Gnomad FIN

AF:

0.801

Gnomad MID

AF:

0.816

Gnomad NFE

AF:

0.763

Gnomad OTH

AF:

0.817

GnomAD4 exome

AF:

0.788

AC:

456906

AN:

579996

Hom.:

180712

Cov.:

AF XY:

0.789

AC XY:

233614

AN XY:

296048

show subpopulations

African (AFR)

AF:

0.931

AC:

13270

AN:

14248

American (AMR)

AF:

0.849

AC:

15552

AN:

18328

Ashkenazi Jewish (ASJ)

AF:

0.804

AC:

11288

AN:

14036

East Asian (EAS)

AF:

0.870

AC:

26953

AN:

30968

South Asian (SAS)

AF:

0.847

AC:

36938

AN:

43636

European-Finnish (FIN)

AF:

0.804

AC:

30155

AN:

37516

Middle Eastern (MID)

AF:

0.793

AC:

1725

AN:

2176

European-Non Finnish (NFE)

AF:

0.764

AC:

297367

AN:

389298

Other (OTH)

AF:

0.794

AC:

23658

AN:

29790

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

4871

9742

14613

19484

24355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4180

8360

12540

16720

20900

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.825

AC:

125545

AN:

152166

Hom.:

52190

Cov.:

AF XY:

0.825

AC XY:

61389

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.928

AC:

38562

AN:

41564

American (AMR)

AF:

0.826

AC:

12643

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.797

AC:

2767

AN:

3472

East Asian (EAS)

AF:

0.870

AC:

4460

AN:

5128

South Asian (SAS)

AF:

0.849

AC:

4097

AN:

4828

European-Finnish (FIN)

AF:

0.801

AC:

8479

AN:

10582

Middle Eastern (MID)

AF:

0.816

AC:

240

AN:

294

European-Non Finnish (NFE)

AF:

0.763

AC:

51831

AN:

67972

Other (OTH)

AF:

0.820

AC:

1734

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1132

2263

3395

4526

5658

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

882

1764

2646

3528

4410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.801

Hom.:

6107

Bravo

AF:

0.831

Asia WGS

AF:

0.883

AC:

3074

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

5.9

(source)

DANN

Benign

0.38

PhyloP100

-0.22

PromoterAI

-0.048

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over