rs6426553

Variant names:

• chr1-226891294-G-T
• rs6426553
• NM_000447.3:c.903G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-226891294-G-T
• chr1-226891294-G-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000447.3(PSEN2):​c.903G>T​(p.Thr301Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00645 in 1,613,904 control chromosomes in the GnomAD database, including 526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (263 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (263 hom.)
• Consequence: PSEN2 NM_000447.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.04
• Publications: 2 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-226891294-G-T is Benign according to our data. Variant chr1-226891294-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

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.903G>T	p.Thr301Thr	synonymous	Exon 10 of 13	NP_000438.2	P49810-1
	PSEN2	NM_001437537.1		c.903G>T	p.Thr301Thr	synonymous	Exon 9 of 12	NP_001424466.1
	PSEN2	NM_012486.3		c.903G>T	p.Thr301Thr	synonymous	Exon 10 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.903G>T	p.Thr301Thr	synonymous	Exon 10 of 13	ENSP00000355747.3	P49810-1
	PSEN2	ENST00000366782.6	TSL:1	c.903G>T	p.Thr301Thr	synonymous	Exon 10 of 13	ENSP00000355746.2	P49810-1
	ENSG00000288674	ENST00000366779.6	TSL:2	n.903G>T		non_coding_transcript_exon	Exon 10 of 32	ENSP00000355741.2

Frequencies

GnomAD3 genomes AF: 0.0325 AC: 4939 AN: 152132 Hom.: 262 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.0248

GnomAD2 exomes AF: 0.00885 AC: 2218 AN: 250506 AF XY: 0.00632

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.00603

Gnomad ASJ exome AF: 0.00487

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000547

Gnomad OTH exome AF: 0.00441

GnomAD4 exome AF: 0.00373 AC: 5459 AN: 1461654 Hom.: 263 Cov.: 34 AF XY: 0.00319 AC XY: 2319 AN XY: 727090

African (AFR) AF: 0.120 AC: 4020 AN: 33466

American (AMR) AF: 0.00693 AC: 310 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00513 AC: 134 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00747 AC: 43 AN: 5756

European-Non Finnish (NFE) AF: 0.000364 AC: 405 AN: 1111968

Other (OTH) AF: 0.00861 AC: 520 AN: 60376

GnomAD4 genome AF: 0.0325 AC: 4954 AN: 152250 Hom.: 263 Cov.: 32 AF XY: 0.0314 AC XY: 2341 AN XY: 74444

African (AFR) AF: 0.111 AC: 4606 AN: 41528

American (AMR) AF: 0.0158 AC: 242 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68018

Other (OTH) AF: 0.0246 AC: 52 AN: 2116

Alfa AF: 0.0104 Hom.: 37

Bravo AF: 0.0380

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Alzheimer disease 4 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Dilated cardiomyopathy 1V (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.010
DANN	Benign	0.64
PhyloP100		-3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=96/4	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: rs6426553; hg19: chr1-227078995;