19-35746008-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_172341.4(PSENEN):c.61+17G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 1,612,446 control chromosomes in the GnomAD database, including 19,635 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.14 ( 1628 hom., cov: 32)

Exomes 𝑓: 0.15 ( 18007 hom. )

Consequence

PSENEN
NM_172341.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.10

Publications

21 publications found

Variant links:

Genes affected

PSENEN (HGNC:30100): (presenilin enhancer, gamma-secretase subunit) Presenilins, which are components of the gamma-secretase protein complex, are required for intramembranous processing of some type I transmembrane proteins, such as the Notch proteins and the beta-amyloid precursor protein. Signaling by Notch receptors mediates a wide range of developmental cell fates. Processing of the beta-amyloid precursor protein generates neurotoxic amyloid beta peptides, the major component of senile plaques associated with Alzheimer's disease. This gene encodes a protein that is required for Notch pathway signaling, and for the activity and accumulation of gamma-secretase. Mutations resulting in haploinsufficiency for this gene cause familial acne inversa-2 (ACNINV2). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

PSENEN Gene-Disease associations (from GenCC):

acne inversa, familial, 2
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Dowling-Degos disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PSENEN links:

ENSG00000188223 (HGNC:):

ENSG00000188223 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 19-35746008-G-C is Benign according to our data. Variant chr19-35746008-G-C is described in ClinVar as [Benign]. Clinvar id is 518298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSENEN	NM_172341.4 link	c.61+17G>C		intron_variant	Intron 2 of 3	ENST00000587708.7	NP_758844.1	Q9NZ42
PSENEN	NM_001281532.3 link	c.61+17G>C		intron_variant	Intron 2 of 3		NP_001268461.1	Q9NZ42

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
PSENEN	ENST00000587708.7 link	c.61+17G>C	intron_variant	Intron 2 of 3	1	NM_172341.4	ENSP00000468411.1	Q9NZ42
PSENEN	ENST00000222266.2 link	c.61+17G>C	intron_variant	Intron 2 of 3	1		ENSP00000222266.1	Q9NZ42
ENSG00000188223	ENST00000591613.2 link	n.61+17G>C	intron_variant	Intron 2 of 10	2		ENSP00000468389.2	K7ERS5
PSENEN	ENST00000591949.1 link	c.61+17G>C	intron_variant	Intron 2 of 2	2		ENSP00000468593.1	K7ES79

Frequencies

GnomAD3 genomes

AF:

0.141

AC:

21414

AN:

152090

Hom.:

1627

Cov.:

show subpopulations

Gnomad AFR

AF:

0.109

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.175

Gnomad ASJ

AF:

0.251

Gnomad EAS

AF:

0.0888

Gnomad SAS

AF:

0.243

Gnomad FIN

AF:

0.0713

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.154

Gnomad OTH

AF:

0.184

GnomAD2 exomes

AF:

0.159

AC:

39857

AN:

250718

AF XY:

0.165

show subpopulations

Gnomad AFR exome

AF:

0.110

Gnomad AMR exome

AF:

0.181

Gnomad ASJ exome

AF:

0.245

Gnomad EAS exome

AF:

0.0812

Gnomad FIN exome

AF:

0.0704

Gnomad NFE exome

AF:

0.160

Gnomad OTH exome

AF:

0.168

GnomAD4 exome

AF:

0.152

AC:

221411

AN:

1460238

Hom.:

18007

Cov.:

AF XY:

0.154

AC XY:

112222

AN XY:

726448

show subpopulations

African (AFR)

AF:

0.111

AC:

3709

AN:

33450

American (AMR)

AF:

0.180

AC:

8054

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.246

AC:

6428

AN:

26124

East Asian (EAS)

AF:

0.0834

AC:

3308

AN:

39682

South Asian (SAS)

AF:

0.234

AC:

20202

AN:

86220

European-Finnish (FIN)

AF:

0.0758

AC:

4038

AN:

53276

Middle Eastern (MID)

AF:

0.236

AC:

1361

AN:

5764

European-Non Finnish (NFE)

AF:

0.149

AC:

165023

AN:

1110676

Other (OTH)

AF:

0.154

AC:

9288

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

9282

18565

27847

37130

46412

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.141

AC:

21426

AN:

152208

Hom.:

1628

Cov.:

AF XY:

0.139

AC XY:

10353

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.109

AC:

4516

AN:

41516

American (AMR)

AF:

0.174

AC:

2668

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.251

AC:

872

AN:

3472

East Asian (EAS)

AF:

0.0888

AC:

460

AN:

5182

South Asian (SAS)

AF:

0.245

AC:

1182

AN:

4828

European-Finnish (FIN)

AF:

0.0713

AC:

756

AN:

10604

Middle Eastern (MID)

AF:

0.296

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.154

AC:

10485

AN:

67996

Other (OTH)

AF:

0.180

AC:

380

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

938

1875

2813

3750

4688

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.162

Hom.:

406

Bravo

AF:

0.143

Asia WGS

AF:

0.170

AC:

592

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Acne inversa, familial, 2

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 15, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.58

PhyloP100

1.1

PromoterAI

0.077

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

19-35746008-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over