1-226888970-T-C

Position:

chr1-226888970-T-C

Variant summary

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

The NM_000447.3(PSEN2):c.708T>C(p.Ser236=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00964 in 1,614,100 control chromosomes in the GnomAD database, including 309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 145 hom., cov: 32)

Exomes 𝑓: 0.0077 ( 164 hom. )

Consequence

PSEN2
NM_000447.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.137

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=-0.54).

BP6

Variant 1-226888970-T-C is Benign according to our data. Variant chr1-226888970-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 256185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-226888970-T-C is described in Lovd as [Benign]. Variant chr1-226888970-T-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.137 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0821 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.708T>C	p.Ser236=	synonymous_variant	8/13	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.708T>C	p.Ser236=	synonymous_variant	8/13	5	NM_000447.3	ENSP00000355747	P4	P49810-1

Frequencies

GnomAD3 genomes

AF:

0.0282

AC:

4292

AN:

152098

Hom.:

145

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0845

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0118

Gnomad ASJ

AF:

0.0184

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00660

Gnomad OTH

AF:

0.0263

GnomAD3 exomes

AF:

0.0118

AC:

2956

AN:

251384

Hom.:

AF XY:

0.00996

AC XY:

1353

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.0905

Gnomad AMR exome

AF:

0.00928

Gnomad ASJ exome

AF:

0.0196

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00474

Gnomad FIN exome

AF:

0.00208

Gnomad NFE exome

AF:

0.00621

Gnomad OTH exome

AF:

0.0114

GnomAD4 exome

AF:

0.00771

AC:

11268

AN:

1461884

Hom.:

164

Cov.:

AF XY:

0.00743

AC XY:

5406

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0841

Gnomad4 AMR exome

AF:

0.00997

Gnomad4 ASJ exome

AF:

0.0206

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00427

Gnomad4 FIN exome

AF:

0.00208

Gnomad4 NFE exome

AF:

0.00568

Gnomad4 OTH exome

AF:

0.0101

GnomAD4 genome

AF:

0.0282

AC:

4297

AN:

152216

Hom.:

145

Cov.:

AF XY:

0.0269

AC XY:

2005

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0845

Gnomad4 AMR

AF:

0.0117

Gnomad4 ASJ

AF:

0.0184

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00415

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00660

Gnomad4 OTH

AF:

0.0260

Alfa

AF:

0.0195

Hom.:

Bravo

AF:

0.0321

Asia WGS

AF:

0.00635

AC:

AN:

3478

EpiCase

AF:

0.00605

EpiControl

AF:

0.00729

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2018	This variant is associated with the following publications: (PMID: 31914229) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

Alzheimer disease 4

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dilated cardiomyopathy 1V

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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

-0.54

CADD

Benign

4.3

DANN

Benign

0.52

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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