NM_000447.3:c.*270C>T

Variant names:

• chr1-226895849-C-T
• rs8383
• NM_000447.3:c.*270C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000447.3(PSEN2):​c.*270C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.507 in 529,464 control chromosomes in the GnomAD database, including 69,053 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18641 hom., cov: 31)
  • Exomes 𝑓: 0.51 (50412 hom.)
• Consequence: PSEN2 NM_000447.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.655
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-226895849-C-T is Benign according to our data. Variant chr1-226895849-C-T is described in ClinVar as Benign. ClinVar VariationId is 296001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.*270C>T		3_prime_UTR	Exon 13 of 13	NP_000438.2	P49810-1
	PSEN2	NM_001437537.1		c.*270C>T		3_prime_UTR	Exon 12 of 12	NP_001424466.1
	PSEN2	NM_012486.3		c.*270C>T		3_prime_UTR	Exon 13 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.*270C>T		3_prime_UTR	Exon 13 of 13	ENSP00000355747.3	P49810-1
	PSEN2	ENST00000366782.6	TSL:1	c.*270C>T		3_prime_UTR	Exon 13 of 13	ENSP00000355746.2	P49810-1
	ENSG00000288674	ENST00000366779.6	TSL:2	n.*270C>T		non_coding_transcript_exon	Exon 13 of 32	ENSP00000355741.2

Frequencies

GnomAD3 genomes AF: 0.491 AC: 74472 AN: 151672 Hom.: 18629 Cov.: 31

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.575

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.619

Gnomad EAS AF: 0.412

Gnomad SAS AF: 0.419

Gnomad FIN AF: 0.545

Gnomad MID AF: 0.666

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.527

GnomAD4 exome AF: 0.513 AC: 193691 AN: 377674 Hom.: 50412 Cov.: 3 AF XY: 0.508 AC XY: 101507 AN XY: 199766

African (AFR) AF: 0.407 AC: 4375 AN: 10744

American (AMR) AF: 0.523 AC: 8537 AN: 16336

Ashkenazi Jewish (ASJ) AF: 0.621 AC: 7000 AN: 11264

East Asian (EAS) AF: 0.449 AC: 10846 AN: 24182

South Asian (SAS) AF: 0.420 AC: 18208 AN: 43358

European-Finnish (FIN) AF: 0.529 AC: 12402 AN: 23436

Middle Eastern (MID) AF: 0.670 AC: 1083 AN: 1616

European-Non Finnish (NFE) AF: 0.532 AC: 119999 AN: 225386

Other (OTH) AF: 0.526 AC: 11241 AN: 21352

GnomAD4 genome AF: 0.491 AC: 74514 AN: 151790 Hom.: 18641 Cov.: 31 AF XY: 0.491 AC XY: 36447 AN XY: 74174

African (AFR) AF: 0.407 AC: 16848 AN: 41392

American (AMR) AF: 0.526 AC: 8020 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 2145 AN: 3468

East Asian (EAS) AF: 0.411 AC: 2115 AN: 5142

South Asian (SAS) AF: 0.420 AC: 2019 AN: 4806

European-Finnish (FIN) AF: 0.545 AC: 5739 AN: 10530

Middle Eastern (MID) AF: 0.661 AC: 193 AN: 292

European-Non Finnish (NFE) AF: 0.527 AC: 35808 AN: 67900

Other (OTH) AF: 0.522 AC: 1104 AN: 2114

Alfa AF: 0.507 Hom.: 7539

Bravo AF: 0.489

Asia WGS AF: 0.419 AC: 1461 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.6
DANN	Benign	0.80
PhyloP100		-0.66
Mutation Taster		=99/1	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: rs8383; hg19: chr1-227083550; COSMIC: COSV60918495; COSMIC: COSV60918495;