rs140501902

Variant names:

• chr1-226883774-C-T
• rs140501902
• NM_000447.3:c.211C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000447.3(PSEN2):​c.211C>T​(p.Arg71Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00367 in 1,614,138 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (25 hom.)
• Consequence: PSEN2 NM_000447.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.50
• Publications: 43 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009556085).
• BP6: Variant 1-226883774-C-T is Benign according to our data. Variant chr1-226883774-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 192130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00337 (513/152264) while in subpopulation NFE AF = 0.0035 (238/68022). AF 95% confidence interval is 0.00313. There are 3 homozygotes in GnomAd4. There are 312 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 513 AD gene.

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.211C>T	p.Arg71Trp	missense	Exon 5 of 13	NP_000438.2	P49810-1
	PSEN2	NM_001437537.1		c.211C>T	p.Arg71Trp	missense	Exon 4 of 12	NP_001424466.1
	PSEN2	NM_012486.3		c.211C>T	p.Arg71Trp	missense	Exon 5 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.211C>T	p.Arg71Trp	missense	Exon 5 of 13	ENSP00000355747.3	P49810-1
	PSEN2	ENST00000366782.6	TSL:1	c.211C>T	p.Arg71Trp	missense	Exon 5 of 13	ENSP00000355746.2	P49810-1
	ENSG00000288674	ENST00000366779.6	TSL:2	n.211C>T		non_coding_transcript_exon	Exon 5 of 32	ENSP00000355741.2

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 513 AN: 152146 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00350

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00357 AC: 898 AN: 251320 AF XY: 0.00357

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0176

Gnomad NFE exome AF: 0.00382

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00370 AC: 5404 AN: 1461874 Hom.: 25 Cov.: 43 AF XY: 0.00354 AC XY: 2577 AN XY: 727236

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.00127 AC: 57 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26136

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

South Asian (SAS) AF: 0.000499 AC: 43 AN: 86258

European-Finnish (FIN) AF: 0.0175 AC: 935 AN: 53406

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00375 AC: 4171 AN: 1112008

Other (OTH) AF: 0.00285 AC: 172 AN: 60396

GnomAD4 genome AF: 0.00337 AC: 513 AN: 152264 Hom.: 3 Cov.: 32 AF XY: 0.00419 AC XY: 312 AN XY: 74436

African (AFR) AF: 0.000554 AC: 23 AN: 41544

American (AMR) AF: 0.00137 AC: 21 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.0207 AC: 220 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00350 AC: 238 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00312 Hom.: 0

Bravo AF: 0.00187

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00335 AC: 407

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00365

EpiControl AF: 0.00385

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	3	Alzheimer disease 4 (3)
-	-	1	Dilated cardiomyopathy 1V (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0096	T
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.0	L
PhyloP100		1.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.0010	B
Vest4		0.28
MVP		0.95
MPC		0.45
ClinPred		0.028	T
GERP RS		2.9
Varity_R		0.15
gMVP		0.33
Mutation Taster		=91/9	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: rs140501902; hg19: chr1-227071475; COSMIC: COSV105222785; COSMIC: COSV105222785;