rs1046240

Variant names:

• chr1-226883824-C-T
• rs1046240
• NM_000447.3:c.261C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000447.3(PSEN2):​c.261C>T​(p.His87His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.511 in 1,613,636 control chromosomes in the GnomAD database, including 213,099 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18328 hom., cov: 31)
  • Exomes 𝑓: 0.51 (194771 hom.)
• Consequence: PSEN2 NM_000447.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.266
• Publications: 30 publications found

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 Gene-Disease associations (from GenCC):

• Alzheimer disease 4

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• early-onset autosomal dominant Alzheimer disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000288674 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 1-226883824-C-T is Benign according to our data. Variant chr1-226883824-C-T is described in ClinVar as Benign. ClinVar VariationId is 256181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.266 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.523 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000447.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSEN2	NM_000447.3	MANE Select	c.261C>T	p.His87His	synonymous	Exon 5 of 13	NP_000438.2	P49810-1
	PSEN2	NM_001437537.1		c.261C>T	p.His87His	synonymous	Exon 4 of 12	NP_001424466.1
	PSEN2	NM_012486.3		c.261C>T	p.His87His	synonymous	Exon 5 of 13	NP_036618.2	P49810-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSEN2	ENST00000366783.8	TSL:5 MANE Select	c.261C>T	p.His87His	synonymous	Exon 5 of 13	ENSP00000355747.3	P49810-1
	PSEN2	ENST00000366782.6	TSL:1	c.261C>T	p.His87His	synonymous	Exon 5 of 13	ENSP00000355746.2	P49810-1
	ENSG00000288674	ENST00000366779.6	TSL:2	n.261C>T		non_coding_transcript_exon	Exon 5 of 32	ENSP00000355741.2

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73748 AN: 151806 Hom.: 18318 Cov.: 31

Gnomad AFR AF: 0.389

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.525

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.414

Gnomad FIN AF: 0.547

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.530

GnomAD2 exomes AF: 0.502 AC: 126306 AN: 251386 AF XY: 0.503

Gnomad AFR exome AF: 0.380

Gnomad AMR exome AF: 0.518

Gnomad ASJ exome AF: 0.613

Gnomad EAS exome AF: 0.405

Gnomad FIN exome AF: 0.536

Gnomad NFE exome AF: 0.534

Gnomad OTH exome AF: 0.555

GnomAD4 exome AF: 0.514 AC: 751560 AN: 1461712 Hom.: 194771 Cov.: 59 AF XY: 0.513 AC XY: 372972 AN XY: 727156

African (AFR) AF: 0.391 AC: 13088 AN: 33476

American (AMR) AF: 0.522 AC: 23357 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.617 AC: 16130 AN: 26136

East Asian (EAS) AF: 0.442 AC: 17530 AN: 39698

South Asian (SAS) AF: 0.416 AC: 35871 AN: 86258

European-Finnish (FIN) AF: 0.534 AC: 28525 AN: 53392

Middle Eastern (MID) AF: 0.656 AC: 3781 AN: 5764

European-Non Finnish (NFE) AF: 0.524 AC: 582219 AN: 1111884

Other (OTH) AF: 0.514 AC: 31059 AN: 60382

GnomAD4 genome AF: 0.486 AC: 73787 AN: 151924 Hom.: 18328 Cov.: 31 AF XY: 0.485 AC XY: 36056 AN XY: 74268

African (AFR) AF: 0.389 AC: 16114 AN: 41420

American (AMR) AF: 0.525 AC: 8016 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 2123 AN: 3466

East Asian (EAS) AF: 0.411 AC: 2115 AN: 5148

South Asian (SAS) AF: 0.416 AC: 2002 AN: 4812

European-Finnish (FIN) AF: 0.547 AC: 5781 AN: 10574

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.527 AC: 35815 AN: 67914

Other (OTH) AF: 0.525 AC: 1108 AN: 2110

Alfa AF: 0.525 Hom.: 33325

Bravo AF: 0.483

Asia WGS AF: 0.415 AC: 1445 AN: 3478

EpiCase AF: 0.538

EpiControl AF: 0.558

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	Alzheimer disease 4 (4)
-	-	2	Dilated cardiomyopathy 1V (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	5.4
DANN	Benign	0.65
PhyloP100		0.27
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1046240; hg19: chr1-227071525; COSMIC: COSV60915252; COSMIC: COSV60915252;