rs61730652

Positions:

• chr1-226888970-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.137

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]

ACMG classification

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	UniProt
PSEN2	NM_000447.3	c.708T>C	p.Ser236=	synonymous_variant	8/13	ENST00000366783.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSEN2	ENST00000366783.8	c.708T>C	p.Ser236=	synonymous_variant	8/13	5	NM_000447.3	P4

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4292 AN: 152098 Hom.: 145 Cov.: 32

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.: 73 AF XY: 0.00996 AC XY: 1353 AN XY: 135884

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.: 32 AF XY: 0.00743 AC XY: 5406 AN XY: 727240

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.: 32 AF XY: 0.0269 AC XY: 2005 AN XY: 74426

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.: 37

Bravo AF: 0.0321

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.00605

EpiControl AF: 0.00729

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2018	This variant is associated with the following publications: (PMID: 31914229) -

Alzheimer disease 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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

Other links and lift over

dbSNP: rs61730652; hg19: chr1-227076671;