1-226888977-A-G

Variant names:

• chr1-226888977-A-G
• rs28936379
• NM_000447.3:c.715A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000447.3(PSEN2):​c.715A>G​(p.Met239Val) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M239I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSEN2 NM_000447.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 9.25
• Publications: 57 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-226888979-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 8850.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859
• PP5: Variant 1-226888977-A-G is Pathogenic according to our data. Variant chr1-226888977-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 8846.Status of the report is criteria_provided_single_submitter, 1 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.715A>G	p.Met239Val	missense	Exon 8 of 13	NP_000438.2
	PSEN2	NM_001437537.1		c.715A>G	p.Met239Val	missense	Exon 7 of 12	NP_001424466.1
	PSEN2	NM_012486.3		c.715A>G	p.Met239Val	missense	Exon 8 of 13	NP_036618.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSEN2	ENST00000366783.8	TSL:5 MANE Select	c.715A>G	p.Met239Val	missense	Exon 8 of 13	ENSP00000355747.3
	PSEN2	ENST00000366782.6	TSL:1	c.715A>G	p.Met239Val	missense	Exon 8 of 13	ENSP00000355746.2
	ENSG00000288674	ENST00000366779.6	TSL:2	n.715A>G		non_coding_transcript_exon	Exon 8 of 32	ENSP00000355741.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000911 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	1.7	L
PhyloP100		9.3
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.88
Sift	Benign	0.034	D
Sift4G	Benign	0.39	T
Polyphen		0.85	P
Vest4		0.93
MutPred		0.64		Gain of glycosylation at S236 (P = 0.2496)
MVP		0.97
MPC		0.69
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.53
gMVP		0.87
Mutation Taster		=1/99	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: rs28936379; hg19: chr1-227076678;