rs186308126

Variant names:

• chr1-226870599-C-T
• rs186308126
• ENST00000366779.6:n.-350+94C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000366779.6(ENSG00000288674):​n.-350+94C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00548 in 151,870 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0055 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENSG00000288674 ENST00000366779.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -1.72
• Publications: 0 publications found

Genes affected

ENSG00000288674 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 1-226870599-C-T is Benign according to our data. Variant chr1-226870599-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 295979.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00548 (833/151870) while in subpopulation AMR AF = 0.0378 (576/15244). AF 95% confidence interval is 0.0352. There are 25 homozygotes in GnomAd4. There are 458 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000366779.6. 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.-400C>T		upstream_gene	N/A	NP_000438.2	P49810-1
	PSEN2	NM_001437537.1		c.-257C>T		upstream_gene	N/A	NP_001424466.1
	PSEN2	NM_012486.3		c.-400C>T		upstream_gene	N/A	NP_036618.2	P49810-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000288674	ENST00000366779.6	TSL:2	n.-350+94C>T		intron	N/A	ENSP00000355741.2
	PSEN2	ENST00000676945.1		c.-400C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000504433.1	A0A7I2V5S6
	PSEN2	ENST00000677599.1		c.-400C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	ENSP00000503673.1	A0A7I2V3R9

Frequencies

GnomAD3 genomes AF: 0.00550 AC: 835 AN: 151762 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0378

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0375

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00864

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 170 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 142

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6

East Asian (EAS) AF: 0.00 AC: 0 AN: 12

South Asian (SAS) AF: 0.00 AC: 0 AN: 6

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 138

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.00548 AC: 833 AN: 151870 Hom.: 25 Cov.: 32 AF XY: 0.00617 AC XY: 458 AN XY: 74264

African (AFR) AF: 0.000650 AC: 27 AN: 41508

American (AMR) AF: 0.0378 AC: 576 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.0374 AC: 193 AN: 5162

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67900

Other (OTH) AF: 0.00855 AC: 18 AN: 2106

Alfa AF: 0.00423 Hom.: 1

Bravo AF: 0.0101

Asia WGS AF: 0.0190 AC: 64 AN: 3364

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Early-onset autosomal dominant Alzheimer disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	8.2
DANN	Benign	0.90
PhyloP100		-1.7
PromoterAI		-0.13	Neutral
Mutation Taster		=300/0	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: rs186308126; hg19: chr1-227058300;