1-226888970-T-G

Variant names:

• chr1-226888970-T-G
• NM_000447.3:c.708T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000447.3(PSEN2):​c.708T>G​(p.Ser236Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S236S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PSEN2 NM_000447.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.137

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]

ENSG00000288674 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity PSN2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000447.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSEN2	NM_000447.3	c.708T>G	p.Ser236Arg	missense_variant	Exon 8 of 13	ENST00000366783.8	NP_000438.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSEN2	ENST00000366783.8	c.708T>G	p.Ser236Arg	missense_variant	Exon 8 of 13	5	NM_000447.3	ENSP00000355747.3
ENSG00000288674	ENST00000366779.6	n.708T>G		non_coding_transcript_exon_variant	Exon 8 of 32	2		ENSP00000355741.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.;.;.;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Pathogenic	0.99	D;D;D;.;D;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H;.;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.1	D;D;D;D;.;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D;D;D;.;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.96
MutPred		0.77		Gain of methylation at S236 (P = 0.0606);Gain of methylation at S236 (P = 0.0606);.;.;.;.;
MVP		0.97
MPC		0.93
ClinPred		1.0	D
GERP RS		-4.3
Varity_R		0.88
gMVP		0.99

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-227076671;