1-226895849-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000447.3(PSEN2):​c.*270C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PSEN2 NM_000447.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

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>A		3_prime_UTR	Exon 13 of 13	NP_000438.2	P49810-1
	PSEN2	NM_001437537.1		c.*270C>A		3_prime_UTR	Exon 12 of 12	NP_001424466.1
	PSEN2	NM_012486.3		c.*270C>A		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>A		3_prime_UTR	Exon 13 of 13	ENSP00000355747.3	P49810-1
	PSEN2	ENST00000366782.6	TSL:1	c.*270C>A		3_prime_UTR	Exon 13 of 13	ENSP00000355746.2	P49810-1
	ENSG00000288674	ENST00000366779.6	TSL:2	n.*270C>A		non_coding_transcript_exon	Exon 13 of 32	ENSP00000355741.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 378486 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 200204

African (AFR) AF: 0.00 AC: 0 AN: 10784

American (AMR) AF: 0.00 AC: 0 AN: 16364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11288

East Asian (EAS) AF: 0.00 AC: 0 AN: 24256

South Asian (SAS) AF: 0.00 AC: 0 AN: 43384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1618

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 225902

Other (OTH) AF: 0.00 AC: 0 AN: 21400

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.7
DANN	Benign	0.76
PhyloP100		-0.66

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;