rs10402601

Positions:

• chr19-35746008-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_172341.4(PSENEN):​c.61+17G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 1,612,446 control chromosomes in the GnomAD database, including 19,635 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1628 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18007 hom.)
• Consequence: PSENEN NM_172341.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.10

Genes affected

PSENEN (HGNC:30100): (presenilin enhancer, gamma-secretase subunit) Presenilins, which are components of the gamma-secretase protein complex, are required for intramembranous processing of some type I transmembrane proteins, such as the Notch proteins and the beta-amyloid precursor protein. Signaling by Notch receptors mediates a wide range of developmental cell fates. Processing of the beta-amyloid precursor protein generates neurotoxic amyloid beta peptides, the major component of senile plaques associated with Alzheimer's disease. This gene encodes a protein that is required for Notch pathway signaling, and for the activity and accumulation of gamma-secretase. Mutations resulting in haploinsufficiency for this gene cause familial acne inversa-2 (ACNINV2). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-35746008-G-C is Benign according to our data. Variant chr19-35746008-G-C is described in ClinVar as [Benign]. Clinvar id is 518298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-35746008-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSENEN	NM_172341.4	c.61+17G>C		intron_variant		ENST00000587708.7
PSENEN	NM_001281532.3	c.61+17G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSENEN	ENST00000587708.7	c.61+17G>C		intron_variant		1	NM_172341.4	P1
PSENEN	ENST00000222266.2	c.61+17G>C		intron_variant		1		P1
PSENEN	ENST00000591949.1	c.61+17G>C		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.141 AC: 21414 AN: 152090 Hom.: 1627 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.0888

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.0713

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.184

GnomAD3 exomes AF: 0.159 AC: 39857 AN: 250718 Hom.: 3487 AF XY: 0.165 AC XY: 22340 AN XY: 135660

Gnomad AFR exome AF: 0.110

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.245

Gnomad EAS exome AF: 0.0812

Gnomad SAS exome AF: 0.234

Gnomad FIN exome AF: 0.0704

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.168

GnomAD4 exome AF: 0.152 AC: 221411 AN: 1460238 Hom.: 18007 Cov.: 32 AF XY: 0.154 AC XY: 112222 AN XY: 726448

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.180

Gnomad4 ASJ exome AF: 0.246

Gnomad4 EAS exome AF: 0.0834

Gnomad4 SAS exome AF: 0.234

Gnomad4 FIN exome AF: 0.0758

Gnomad4 NFE exome AF: 0.149

Gnomad4 OTH exome AF: 0.154

GnomAD4 genome AF: 0.141 AC: 21426 AN: 152208 Hom.: 1628 Cov.: 32 AF XY: 0.139 AC XY: 10353 AN XY: 74432

Gnomad4 AFR AF: 0.109

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.251

Gnomad4 EAS AF: 0.0888

Gnomad4 SAS AF: 0.245

Gnomad4 FIN AF: 0.0713

Gnomad4 NFE AF: 0.154

Gnomad4 OTH AF: 0.180

Alfa AF: 0.162 Hom.: 406

Bravo AF: 0.143

Asia WGS AF: 0.170 AC: 592 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acne inversa, familial, 2 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Oct 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jan 15, 2016	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs10402601; hg19: chr19-36236909; COSMIC: COSV53074159; COSMIC: COSV53074159;