rs3177404

Variant names:

• chr1-226875528-C-T
• rs7961
• ENST00000366779.6:n.-43C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000366779.6(ENSG00000288674):​n.-43C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.077 in 152,188 control chromosomes in the GnomAD database, including 1,198 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.077 (1198 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENSG00000288674 ENST00000366779.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.271
• Publications: 1 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: 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: LIMITED Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-226875528-C-T is Benign according to our data. Variant chr1-226875528-C-T is described in ClinVar as Benign. ClinVar VariationId is 295986.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSEN2	NM_000447.3	MANE Select	c.-43C>T		5_prime_UTR	Exon 3 of 13	NP_000438.2
	PSEN2	NM_001437537.1		c.-43C>T		5_prime_UTR	Exon 2 of 12	NP_001424466.1
	PSEN2	NM_012486.3		c.-43C>T		5_prime_UTR	Exon 3 of 13	NP_036618.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000288674	ENST00000366779.6	TSL:2	n.-43C>T		non_coding_transcript_exon	Exon 3 of 32	ENSP00000355741.2
	PSEN2	ENST00000366783.8	TSL:5 MANE Select	c.-43C>T		5_prime_UTR	Exon 3 of 13	ENSP00000355747.3
	PSEN2	ENST00000366782.6	TSL:1	c.-299C>T		5_prime_UTR	Exon 2 of 13	ENSP00000355746.2

Frequencies

GnomAD3 genomes AF: 0.0768 AC: 11684 AN: 152072 Hom.: 1194 Cov.: 32

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0550

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.0567

Gnomad SAS AF: 0.0588

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.0635

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 28 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 22

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 16

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

GnomAD4 genome AF: 0.0770 AC: 11721 AN: 152188 Hom.: 1198 Cov.: 32 AF XY: 0.0763 AC XY: 5674 AN XY: 74402

African (AFR) AF: 0.236 AC: 9803 AN: 41470

American (AMR) AF: 0.0548 AC: 839 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3472

East Asian (EAS) AF: 0.0570 AC: 295 AN: 5172

South Asian (SAS) AF: 0.0591 AC: 285 AN: 4822

European-Finnish (FIN) AF: 0.00254 AC: 27 AN: 10610

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00309 AC: 210 AN: 68024

Other (OTH) AF: 0.0629 AC: 133 AN: 2116

Alfa AF: 0.0364 Hom.: 1124

Bravo AF: 0.0878

Asia WGS AF: 0.0610 AC: 212 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Alzheimer disease 4 (1)
-	-	1	Dilated cardiomyopathy 1V (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.2
DANN	Benign	0.69
PhyloP100		-0.27
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7961; hg19: chr1-227063229;