NM_000447.3:c.185G>A

Variant names:

• chr1-226883748-G-A
• rs58973334
• NM_000447.3:c.185G>A

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.185G>A​(p.Arg62His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00541 in 1,614,112 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R62C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (121 hom.)
• Consequence: PSEN2 NM_000447.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: -1.50
• Publications: 57 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=0.0026604533).
• BP6: Variant 1-226883748-G-A is Benign according to our data. Variant chr1-226883748-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 97995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.014 (2130/152284) while in subpopulation AFR AF = 0.0398 (1652/41538). AF 95% confidence interval is 0.0382. There are 35 homozygotes in GnomAd4. There are 1054 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2130 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.185G>A	p.Arg62His	missense	Exon 5 of 13	NP_000438.2	P49810-1
	PSEN2	NM_001437537.1		c.185G>A	p.Arg62His	missense	Exon 4 of 12	NP_001424466.1
	PSEN2	NM_012486.3		c.185G>A	p.Arg62His	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.185G>A	p.Arg62His	missense	Exon 5 of 13	ENSP00000355747.3	P49810-1
	PSEN2	ENST00000366782.6	TSL:1	c.185G>A	p.Arg62His	missense	Exon 5 of 13	ENSP00000355746.2	P49810-1
	ENSG00000288674	ENST00000366779.6	TSL:2	n.185G>A		non_coding_transcript_exon	Exon 5 of 32	ENSP00000355741.2

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2120 AN: 152168 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0214

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.00861 AC: 2161 AN: 251116 AF XY: 0.00918

Gnomad AFR exome AF: 0.0402

Gnomad AMR exome AF: 0.00645

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00244

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.00451 AC: 6595 AN: 1461828 Hom.: 121 Cov.: 43 AF XY: 0.00525 AC XY: 3818 AN XY: 727208

African (AFR) AF: 0.0468 AC: 1568 AN: 33478

American (AMR) AF: 0.00662 AC: 296 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0178 AC: 464 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0264 AC: 2278 AN: 86256

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53384

Middle Eastern (MID) AF: 0.0250 AC: 144 AN: 5754

European-Non Finnish (NFE) AF: 0.00116 AC: 1286 AN: 1112006

Other (OTH) AF: 0.00906 AC: 547 AN: 60390

GnomAD4 genome AF: 0.0140 AC: 2130 AN: 152284 Hom.: 35 Cov.: 32 AF XY: 0.0142 AC XY: 1054 AN XY: 74486

African (AFR) AF: 0.0398 AC: 1652 AN: 41538

American (AMR) AF: 0.00843 AC: 129 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0216 AC: 104 AN: 4820

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00194 AC: 132 AN: 68024

Other (OTH) AF: 0.0166 AC: 35 AN: 2112

Alfa AF: 0.00663 Hom.: 27

Bravo AF: 0.0147

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.0374 AC: 165

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00988 AC: 1200

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00451

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (5)
-	-	4	not specified (4)
-	-	3	Alzheimer disease 4 (3)
-	-	1	Alzheimer disease (1)
-	-	1	Dilated cardiomyopathy 1V (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	8.0
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0027	T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Benign	0.20	N
PhyloP100		-1.5
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.29
Sift	Benign	0.21	T
Sift4G	Benign	0.23	T
Polyphen		0.0010	B
Vest4		0.083
MVP		0.82
MPC		0.30
ClinPred		0.0090	T
GERP RS		-4.6
Varity_R		0.021
gMVP		0.22
Mutation Taster		=100/0	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: rs58973334; hg19: chr1-227071449;