chr1-226885570-C-T

Position:

• chr1-226885570-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4 BP6_Very_Strong BS1 BS2

The NM_000447.3(PSEN2):​c.389C>T​(p.Ser130Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0012 in 1,614,032 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S130S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00071 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: PSEN2 NM_000447.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2 B:7 O:1
• Conservation: PhyloP100: 4.68

Genes affected

PSEN2 (HGNC:9509): (presenilin 2) Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1 or PSEN2) or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor such that, they either directly regulate gamma-secretase activity, or themselves act are protease enzymes. Two alternatively spliced transcript variants encoding different isoforms of PSEN2 have been identified. [provided by RefSeq, Jul 2008]

ENSG00000288674 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3652564).
• BP6: Variant 1-226885570-C-T is Benign according to our data. Variant chr1-226885570-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 8852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-226885570-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000709 (108/152252) while in subpopulation NFE AF= 0.00122 (83/68012). AF 95% confidence interval is 0.00101. There are 0 homozygotes in gnomad4. There are 55 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 108 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSEN2	NM_000447.3	c.389C>T	p.Ser130Leu	missense_variant	6/13	ENST00000366783.8	NP_000438.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSEN2	ENST00000366783.8	c.389C>T	p.Ser130Leu	missense_variant	6/13	5	NM_000447.3	ENSP00000355747.3
ENSG00000288674	ENST00000366779.6	n.389C>T		non_coding_transcript_exon_variant	6/32	2		ENSP00000355741.2

Frequencies

GnomAD3 genomes AF: 0.000710 AC: 108 AN: 152134 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000677 AC: 170 AN: 251112 Hom.: 0 AF XY: 0.000722 AC XY: 98 AN XY: 135740

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00125 AC: 1830 AN: 1461780 Hom.: 3 Cov.: 31 AF XY: 0.00126 AC XY: 915 AN XY: 727190

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00155

Gnomad4 OTH exome AF: 0.000994

GnomAD4 genome AF: 0.000709 AC: 108 AN: 152252 Hom.: 0 Cov.: 31 AF XY: 0.000739 AC XY: 55 AN XY: 74430

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00123 Hom.: 0

Bravo AF: 0.000627

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000634 AC: 77

EpiCase AF: 0.00131

EpiControl AF: 0.00166

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:2 Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alzheimer disease 4 Pathogenic:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2006	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Dilated cardiomyopathy 1V Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2006	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 25, 2024	Variant summary: PSEN2 c.389C>T (p.Ser130Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 1607058 control chromosomes, predominantly at a frequency of 0.0015 within the Non-Finnish European subpopulation in the gnomAD database (v4.1 dataset), including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in PSEN2 causing Alzheimer Disease 4 phenotype. c.389C>T has been reported in the literature in individuals affected with Alzheimer Disease (e.g. Tedde_2003). However, at least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated that the variant didn't alter amyloid beta (Abeta) peptide generation from beta-amyloid precursor protein (APP), suggesting that the variant represent a polymorphisms rather than disease-causing mutation (Walker_2005). In addition, the variant was also reported in individuals affected with idiopathic dilated cardiomyopathy (Li_2006), however current evidence is not sufficient to support the association of PSEN2 with this phenotype. The following publications have been ascertained in the context of this evaluation (PMID: 14623725, 15663477, 7186461, 20375137). ClinVar contains an entry for this variant (Variation ID: 8852). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 30, 2020	- -

PSEN2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 15, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Alzheimer disease Benign:1

Likely benign, criteria provided, single submitter

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

- -

not provided Other:1

not provided, no classification provided

literature only

VIB Department of Molecular Genetics, University of Antwerp

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;.;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M;.;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.5	D;D;D;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.012	D;D;D;.
Sift4G	Uncertain	0.020	D;D;D;D
Polyphen		0.95	P;.;.;.
Vest4		0.74
MVP		0.98
MPC		0.60
ClinPred		0.18	T
GERP RS		5.1
Varity_R		0.56
gMVP		0.83

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

LitVar

Other links and lift over

dbSNP: rs63750197; hg19: chr1-227073271;