rs63750215

Variant names:

• chr1-226885603-A-T
• rs63750215
• NM_000447.3:c.422A>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM2 PP3_Strong PP5_Very_Strong

The NM_000447.3(PSEN2):​c.422A>T​(p.Asn141Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000762646: Experimental studies have shown that this missense change affects PSEN2 function (PMID:8986743, 9050898, 15663477, 16959576, 20634584, 21234330, 22115042, 22249458)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N141D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PSEN2 NM_000447.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:2
• Conservation: PhyloP100: 9.05
• Publications: 332 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: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000762646: Experimental studies have shown that this missense change affects PSEN2 function (PMID: 8986743, 9050898, 15663477, 16959576, 20634584, 21234330, 22115042, 22249458).; SCV004813595: The variant alters PSEN2 function (e.g. Tu_2006, Nam_2022). PMID: 26166204, 16533963, 35418126, 16959576; SCV001145229: Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 9050898, 10846187, 15663477, 22249458, 31020001, 35992913); SCV002513134: "Published functional studies demonstrate N141I resulted in impaired secretase activity as well as exaggerated inflammatory cytokine release, NFKB activity, and A-beta internalization (Fung et al., 2020);"
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 1-226885603-A-T is Pathogenic according to our data. Variant chr1-226885603-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 8845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.422A>T	p.Asn141Ile	missense	Exon 6 of 13	NP_000438.2	P49810-1
	PSEN2	NM_001437537.1		c.422A>T	p.Asn141Ile	missense	Exon 5 of 12	NP_001424466.1
	PSEN2	NM_012486.3		c.422A>T	p.Asn141Ile	missense	Exon 6 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.422A>T	p.Asn141Ile	missense	Exon 6 of 13	ENSP00000355747.3	P49810-1
	PSEN2	ENST00000366782.6	TSL:1	c.422A>T	p.Asn141Ile	missense	Exon 6 of 13	ENSP00000355746.2	P49810-1
	ENSG00000288674	ENST00000366779.6	TSL:2	n.422A>T		non_coding_transcript_exon	Exon 6 of 32	ENSP00000355741.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Alzheimer disease 4 (6)
3	-	-	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.3	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.052	T
Polyphen		0.93	P
Vest4		0.96
MutPred		0.83		Loss of catalytic residue at S138 (P = 0.3572)
MVP		0.99
MPC		0.90
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.89
gMVP		0.99
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs63750215; hg19: chr1-227073304;