1-226871336-C-T

Variant names:

• chr1-226871336-C-T
• rs1295645
• ENST00000366779.6:n.-275C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000366779.6(ENSG00000288674):​n.-275C>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 0.157 in 152,224 control chromosomes in the GnomAD database, including 2,289 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2287 hom., cov: 32)
  • Exomes 𝑓: 0.19 (2 hom.)
• Consequence: ENSG00000288674 ENST00000366779.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.467
• Publications: 9 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-226871336-C-T is Benign according to our data. Variant chr1-226871336-C-T is described in ClinVar as [Benign]. Clinvar id is 295983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSEN2	NM_000447.3	c.-275C>T		5_prime_UTR_variant	Exon 2 of 13	ENST00000366783.8	NP_000438.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000288674	ENST00000366779.6	n.-275C>T		non_coding_transcript_exon_variant	Exon 2 of 32	2		ENSP00000355741.2
PSEN2	ENST00000366783.8	c.-275C>T		5_prime_UTR_variant	Exon 2 of 13	5	NM_000447.3	ENSP00000355747.3
ENSG00000288674	ENST00000366779.6	n.-275C>T		5_prime_UTR_variant	Exon 2 of 32	2		ENSP00000355741.2

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23819 AN: 152034 Hom.: 2285 Cov.: 32

Gnomad AFR AF: 0.0448

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.174

GnomAD4 exome AF: 0.194 AC: 14 AN: 72 Hom.: 2 Cov.: 0 AF XY: 0.217 AC XY: 13 AN XY: 60

African (AFR) AC: 0 AN: 0

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

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 1 AN: 4

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.167 AC: 1 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.212 AC: 11 AN: 52

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.157 AC: 23818 AN: 152152 Hom.: 2287 Cov.: 32 AF XY: 0.156 AC XY: 11607 AN XY: 74400

African (AFR) AF: 0.0448 AC: 1862 AN: 41524

American (AMR) AF: 0.186 AC: 2845 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 710 AN: 3472

East Asian (EAS) AF: 0.248 AC: 1282 AN: 5168

South Asian (SAS) AF: 0.173 AC: 831 AN: 4816

European-Finnish (FIN) AF: 0.147 AC: 1558 AN: 10598

Middle Eastern (MID) AF: 0.168 AC: 49 AN: 292

European-Non Finnish (NFE) AF: 0.207 AC: 14083 AN: 67984

Other (OTH) AF: 0.174 AC: 366 AN: 2108

Alfa AF: 0.188 Hom.: 4033

Bravo AF: 0.149

Asia WGS AF: 0.183 AC: 639 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Dilated cardiomyopathy 1V Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Alzheimer disease 4 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.7
DANN	Benign	0.58
PhyloP100		0.47
PromoterAI		0.00060	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs1295645; hg19: chr1-227059037;