Genetic Variant PENK:c.138+400C>T (chr8-56445416-G-A) – 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.138+400C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 443,382 control chromosomes in the GnomAD database, including 41,561 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 0.39 ( 12078 hom., cov: 32)

Exomes 𝑓: 0.44 ( 29483 hom. )

Consequence

PENK
NM_001135690.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.515

Publications

8 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:

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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=-0.84).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135690.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PENK	NM_001135690.3	MANE Select	c.138+400C>T		intron	N/A	NP_001129162.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PENK	ENST00000451791.7	TSL:1 MANE Select	c.138+400C>T	intron	N/A	ENSP00000400894.2
PENK	ENST00000314922.3	TSL:1	c.138+400C>T	intron	N/A	ENSP00000324248.3
PENK	ENST00000518770.1	TSL:2	c.*259C>T	3_prime_UTR	Exon 3 of 3	ENSP00000430592.1

Frequencies

GnomAD3 genomes

AF:

0.386

AC:

58579

AN:

151912

Hom.:

12070

Cov.:

show subpopulations

Gnomad AFR

AF:

0.241

Gnomad AMI

AF:

0.405

Gnomad AMR

AF:

0.356

Gnomad ASJ

AF:

0.492

Gnomad EAS

AF:

0.352

Gnomad SAS

AF:

0.470

Gnomad FIN

AF:

0.535

Gnomad MID

AF:

0.497

Gnomad NFE

AF:

0.447

Gnomad OTH

AF:

0.392

GnomAD4 exome

AF:

0.444

AC:

129274

AN:

291352

Hom.:

29483

Cov.:

AF XY:

0.446

AC XY:

66362

AN XY:

148778

show subpopulations

African (AFR)

AF:

0.255

AC:

2381

AN:

9328

American (AMR)

AF:

0.378

AC:

4395

AN:

11618

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

5118

AN:

10228

East Asian (EAS)

AF:

0.353

AC:

9041

AN:

25638

South Asian (SAS)

AF:

0.502

AC:

4742

AN:

9440

European-Finnish (FIN)

AF:

0.522

AC:

11641

AN:

22304

Middle Eastern (MID)

AF:

0.510

AC:

746

AN:

1464

European-Non Finnish (NFE)

AF:

0.455

AC:

83086

AN:

182720

Other (OTH)

AF:

0.436

AC:

8124

AN:

18612

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

3424

6848

10271

13695

17119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

450

900

1350

1800

2250

<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:

0.386

AC:

58608

AN:

152030

Hom.:

12078

Cov.:

AF XY:

0.388

AC XY:

28866

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.241

AC:

10018

AN:

41488

American (AMR)

AF:

0.356

AC:

5444

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.492

AC:

1705

AN:

3468

East Asian (EAS)

AF:

0.353

AC:

1820

AN:

5162

South Asian (SAS)

AF:

0.472

AC:

2263

AN:

4796

European-Finnish (FIN)

AF:

0.535

AC:

5656

AN:

10568

Middle Eastern (MID)

AF:

0.490

AC:

142

AN:

290

European-Non Finnish (NFE)

AF:

0.447

AC:

30365

AN:

67956

Other (OTH)

AF:

0.391

AC:

826

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1784

3568

5352

7136

8920

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

554

1108

1662

2216

2770

<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:

0.422

Hom.:

3378

Bravo

AF:

0.366

Asia WGS

AF:

0.413

AC:

1439

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

4.0

(source)

DANN

Benign

0.69

PhyloP100

-0.52

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over