dbSNP rs200510037: PSENEN:p.Leu14Val (chr19-35745970-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_172341.4(PSENEN):c.40C>G(p.Leu14Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L14L) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PSENEN
NM_172341.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.29

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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSENEN	NM_172341.4 link	c.40C>G	p.Leu14Val	missense_variant	Exon 2 of 4	ENST00000587708.7	NP_758844.1	Q9NZ42
PSENEN	NM_001281532.3 link	c.40C>G	p.Leu14Val	missense_variant	Exon 2 of 4		NP_001268461.1	Q9NZ42

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PSENEN	ENST00000587708.7 link	c.40C>G	p.Leu14Val	missense_variant	Exon 2 of 4	1	NM_172341.4	ENSP00000468411.1	Q9NZ42
PSENEN	ENST00000222266.2 link	c.40C>G	p.Leu14Val	missense_variant	Exon 2 of 4	1		ENSP00000222266.1	Q9NZ42
ENSG00000188223	ENST00000591613.2 link	n.40C>G		non_coding_transcript_exon_variant	Exon 2 of 11	2		ENSP00000468389.2	K7ERS5
PSENEN	ENST00000591949.1 link	c.40C>G	p.Leu14Val	missense_variant	Exon 2 of 3	2		ENSP00000468593.1	K7ES79

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112004

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;.;D

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

.;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.88

D;D;D

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.6

M;.;M

PhyloP100

3.3

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.5

.;.;N

REVEL

Pathogenic

0.70

Sift

Benign

0.078

.;.;T

Sift4G

Benign

0.084

T;T;T

Polyphen

1.0

D;.;D

Vest4

0.54

MutPred

0.88

Loss of ubiquitination at K17 (P = 0.1741);Loss of ubiquitination at K17 (P = 0.1741);Loss of ubiquitination at K17 (P = 0.1741);

MVP

0.84

MPC

1.5

ClinPred

0.98

GERP RS

4.4

PromoterAI

-0.00040

Neutral

(source)

Varity_R

0.72

gMVP

0.77

Mutation Taster

=23/77

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over