NM_000447.3:c.708T>C

Variant names:

• chr1-226888970-T-C
• rs61730652
• NM_000447.3:c.708T>C

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.708T>C​(p.Ser236Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00964 in 1,614,100 control chromosomes in the GnomAD database, including 309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (145 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (164 hom.)
• Consequence: PSEN2 NM_000447.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.137
• Publications: 5 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=-0.54).
• BP6: Variant 1-226888970-T-C is Benign according to our data. Variant chr1-226888970-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.137 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0821 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.708T>C	p.Ser236Ser	synonymous	Exon 8 of 13	NP_000438.2	P49810-1
	PSEN2	NM_001437537.1		c.708T>C	p.Ser236Ser	synonymous	Exon 7 of 12	NP_001424466.1
	PSEN2	NM_012486.3		c.708T>C	p.Ser236Ser	synonymous	Exon 8 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.708T>C	p.Ser236Ser	synonymous	Exon 8 of 13	ENSP00000355747.3	P49810-1
	PSEN2	ENST00000366782.6	TSL:1	c.708T>C	p.Ser236Ser	synonymous	Exon 8 of 13	ENSP00000355746.2	P49810-1
	ENSG00000288674	ENST00000366779.6	TSL:2	n.708T>C		non_coding_transcript_exon	Exon 8 of 32	ENSP00000355741.2

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 4292 AN: 152098 Hom.: 145 Cov.: 32

Gnomad AFR AF: 0.0845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0184

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00660

Gnomad OTH AF: 0.0263

GnomAD2 exomes AF: 0.0118 AC: 2956 AN: 251384 AF XY: 0.00996

Gnomad AFR exome AF: 0.0905

Gnomad AMR exome AF: 0.00928

Gnomad ASJ exome AF: 0.0196

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00208

Gnomad NFE exome AF: 0.00621

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.00771 AC: 11268 AN: 1461884 Hom.: 164 Cov.: 32 AF XY: 0.00743 AC XY: 5406 AN XY: 727240

African (AFR) AF: 0.0841 AC: 2814 AN: 33478

American (AMR) AF: 0.00997 AC: 446 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0206 AC: 538 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00427 AC: 368 AN: 86258

European-Finnish (FIN) AF: 0.00208 AC: 111 AN: 53420

Middle Eastern (MID) AF: 0.0116 AC: 67 AN: 5768

European-Non Finnish (NFE) AF: 0.00568 AC: 6316 AN: 1112008

Other (OTH) AF: 0.0101 AC: 608 AN: 60396

GnomAD4 genome AF: 0.0282 AC: 4297 AN: 152216 Hom.: 145 Cov.: 32 AF XY: 0.0269 AC XY: 2005 AN XY: 74426

African (AFR) AF: 0.0845 AC: 3505 AN: 41502

American (AMR) AF: 0.0117 AC: 179 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 64 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4822

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10614

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00660 AC: 449 AN: 68012

Other (OTH) AF: 0.0260 AC: 55 AN: 2114

Alfa AF: 0.0125 Hom.: 64

Bravo AF: 0.0321

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.00605

EpiControl AF: 0.00729

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.3
DANN	Benign	0.52
PhyloP100		0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=87/13	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: rs61730652; hg19: chr1-227076671;