chr19-35746494-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_172341.4(PSENEN):c.137C>A(p.Ala46Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A46A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

PSENEN
NM_172341.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.12

Publications

0 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: Likely_benign. The variant received -4 ACMG points.

PM1

In a mutagenesis_site No effect. (size 0) in uniprot entity PEN2_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.22091436).

BS2

High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSENEN	NM_172341.4 link	c.137C>A	p.Ala46Asp	missense_variant	Exon 3 of 4	ENST00000587708.7	NP_758844.1	Q9NZ42
PSENEN	NM_001281532.3 link	c.137C>A	p.Ala46Asp	missense_variant	Exon 3 of 4		NP_001268461.1	Q9NZ42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PSENEN	ENST00000587708.7 link	c.137C>A	p.Ala46Asp	missense_variant	Exon 3 of 4	1	NM_172341.4	ENSP00000468411.1	Q9NZ42
PSENEN	ENST00000222266.2 link	c.137C>A	p.Ala46Asp	missense_variant	Exon 3 of 4	1		ENSP00000222266.1	Q9NZ42
ENSG00000188223	ENST00000591613.2 link	n.137C>A		non_coding_transcript_exon_variant	Exon 3 of 11	2		ENSP00000468389.2	K7ERS5
PSENEN	ENST00000591949.1 link	c.137C>A	p.Ala46Asp	missense_variant	Exon 3 of 3	2		ENSP00000468593.1	K7ES79

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251378

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461674

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727154

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000731

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111936

Other (OTH)

AF:

0.0000331

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 02, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.137C>A (p.A46D) alteration is located in exon 3 (coding exon 2) of the PSENEN gene. This alteration results from a C to A substitution at nucleotide position 137, causing the alanine (A) at amino acid position 46 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jan 18, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces alanine with aspartic acid at codon 46 of the PSENEN protein (p.Ala46Asp). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is present in population databases (rs749446715, ExAC 0.02%). This variant has not been reported in the literature in individuals with PSENEN-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.43

T;.;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.87

.;D;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.8

L;.;L

PhyloP100

3.1

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.5

.;.;N

REVEL

Uncertain

0.31

Sift

Benign

0.29

.;.;T

Sift4G

Benign

0.60

T;T;T

Polyphen

0.0050

B;.;B

Vest4

0.41

MutPred

0.49

Gain of solvent accessibility (P = 0.1154);Gain of solvent accessibility (P = 0.1154);Gain of solvent accessibility (P = 0.1154);

MVP

0.75

MPC

0.93

ClinPred

0.13

GERP RS

4.4

Varity_R

0.40

gMVP

0.82

Mutation Taster

=65/35

polymorphism

(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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chr19-35746494-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over