1-226881945-T-C

Variant names:

• chr1-226881945-T-C
• rs766853710
• NM_000447.3:c.38T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000447.3(PSEN2):​c.38T>C​(p.Val13Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PSEN2 NM_000447.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.812
• 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: 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19893056).

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.38T>C	p.Val13Ala	missense	Exon 4 of 13	NP_000438.2	P49810-1
	PSEN2	NM_001437537.1		c.38T>C	p.Val13Ala	missense	Exon 3 of 12	NP_001424466.1
	PSEN2	NM_012486.3		c.38T>C	p.Val13Ala	missense	Exon 4 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.38T>C	p.Val13Ala	missense	Exon 4 of 13	ENSP00000355747.3	P49810-1
	PSEN2	ENST00000366782.6	TSL:1	c.38T>C	p.Val13Ala	missense	Exon 4 of 13	ENSP00000355746.2	P49810-1
	ENSG00000288674	ENST00000366779.6	TSL:2	n.38T>C		non_coding_transcript_exon	Exon 4 of 32	ENSP00000355741.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461766 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Alzheimer disease 4 (2)
-	1	-	Dilated cardiomyopathy 1V (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.73	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	0.34	N
PhyloP100		0.81
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.42
Sift	Benign	0.76	T
Sift4G	Benign	0.62	T
Polyphen		0.060	B
Vest4		0.059
MutPred		0.062		Loss of stability (P = 0.1959)
MVP		0.94
MPC		0.29
ClinPred		0.29	T
GERP RS		1.6
Varity_R		0.013
gMVP		0.094
Mutation Taster		=95/5	polymorphism

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: rs766853710; hg19: chr1-227069646;