1-226891294-G-T

Position:

chr1-226891294-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000447.3(PSEN2):c.903G>T(p.Thr301=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00645 in 1,613,904 control chromosomes in the GnomAD database, including 526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 263 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 263 hom. )

Consequence

PSEN2
NM_000447.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -3.04

Variant links:

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]

PSEN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 1-226891294-G-T is Benign according to our data. Variant chr1-226891294-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 256187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-226891294-G-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-3.04 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSEN2	NM_000447.3 linkuse as main transcript	c.903G>T	p.Thr301=	synonymous_variant	10/13	ENST00000366783.8	NP_000438.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSEN2	ENST00000366783.8 linkuse as main transcript	c.903G>T	p.Thr301=	synonymous_variant	10/13	5	NM_000447.3	ENSP00000355747	P4	P49810-1

Frequencies

GnomAD3 genomes

AF:

0.0325

AC:

4939

AN:

152132

Hom.:

262

Cov.:

show subpopulations

Gnomad AFR

AF:

0.111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0158

Gnomad ASJ

AF:

0.00547

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.0248

GnomAD3 exomes

AF:

0.00885

AC:

2218

AN:

250506

Hom.:

112

AF XY:

0.00632

AC XY:

856

AN XY:

135462

show subpopulations

Gnomad AFR exome

AF:

0.115

Gnomad AMR exome

AF:

0.00603

Gnomad ASJ exome

AF:

0.00487

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000361

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000547

Gnomad OTH exome

AF:

0.00441

GnomAD4 exome

AF:

0.00373

AC:

5459

AN:

1461654

Hom.:

263

Cov.:

AF XY:

0.00319

AC XY:

2319

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.120

Gnomad4 AMR exome

AF:

0.00693

Gnomad4 ASJ exome

AF:

0.00513

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000313

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000364

Gnomad4 OTH exome

AF:

0.00861

GnomAD4 genome

AF:

0.0325

AC:

4954

AN:

152250

Hom.:

263

Cov.:

AF XY:

0.0314

AC XY:

2341

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.111

Gnomad4 AMR

AF:

0.0158

Gnomad4 ASJ

AF:

0.00547

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.0246

Alfa

AF:

0.00930

Hom.:

Bravo

AF:

0.0380

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Alzheimer disease 4

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Dilated cardiomyopathy 1V

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.010

DANN

Benign

0.64

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over