rs63750048

Variant names:

• chr1-226883817-C-T
• rs63750048
• NM_000447.3:c.254C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 5P and 5B. PP3_Strong PP5 BS1_Supporting BS2

The NM_000447.3(PSEN2):​c.254C>T​(p.Ala85Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A85A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: PSEN2 NM_000447.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.84
• Publications: 23 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: LIMITED Submitted by: ClinGen

ENSG00000288674 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 1-226883817-C-T is Pathogenic according to our data. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-226883817-C-T is described in CliVar as Pathogenic. Clinvar id is 8853.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000103 (15/1461860) while in subpopulation EAS AF = 0.000151 (6/39700). AF 95% confidence interval is 0.0000651. There are 0 homozygotes in GnomAdExome4. There are 10 alleles in the male GnomAdExome4 subpopulation. Median coverage is 43. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSEN2	NM_000447.3	c.254C>T	p.Ala85Val	missense_variant	Exon 5 of 13	ENST00000366783.8	NP_000438.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSEN2	ENST00000366783.8	c.254C>T	p.Ala85Val	missense_variant	Exon 5 of 13	5	NM_000447.3	ENSP00000355747.3
ENSG00000288674	ENST00000366779.6	n.254C>T		non_coding_transcript_exon_variant	Exon 5 of 32	2		ENSP00000355741.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251424 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461860 Hom.: 0 Cov.: 43 AF XY: 0.0000138 AC XY: 10 AN XY: 727232

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000172 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Alzheimer disease 4 Pathogenic:1

Apr 22, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Other:1

-

VIB Department of Molecular Genetics, University of Antwerp

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;.;.;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	2.9	M;.;M;.;.
PhyloP100		7.8
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.6	D;D;D;D;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.010	D;D;D;D;.
Sift4G	Uncertain	0.037	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.81
MutPred		0.94		Gain of ubiquitination at K86 (P = 0.0837);Gain of ubiquitination at K86 (P = 0.0837);Gain of ubiquitination at K86 (P = 0.0837);.;.;
MVP		0.98
MPC		0.68
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.53
gMVP		0.71
Mutation Taster		=0/100	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: rs63750048; hg19: chr1-227071518; COSMIC: COSV60918892;