1-226885569-TC-CT

Variant names:

• chr1-226885569-TC-CT
• NM_000447.3:c.388_389delTCinsCT
• PSEN2 p.Ser130Leu

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_000447.3(PSEN2):​c.388_389delTCinsCT​(p.Ser130Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S130S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PSEN2 NM_000447.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.68
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000447.3

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.388_389delTCinsCT	p.Ser130Leu	missense	N/A	NP_000438.2	P49810-1
	PSEN2	NM_001437537.1		c.388_389delTCinsCT	p.Ser130Leu	missense	N/A	NP_001424466.1
	PSEN2	NM_012486.3		c.388_389delTCinsCT	p.Ser130Leu	missense	N/A	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.388_389delTCinsCT	p.Ser130Leu	missense	N/A	ENSP00000355747.3	P49810-1
	PSEN2	ENST00000366782.6	TSL:1	c.388_389delTCinsCT	p.Ser130Leu	missense	N/A	ENSP00000355746.2	P49810-1
	ENSG00000288674	ENST00000366779.6	TSL:2	n.388_389delTCinsCT		non_coding_transcript_exon	Exon 6 of 32	ENSP00000355741.2

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-227073270;