chr19-35746008-G-C

Variant names:

• chr19-35746008-G-C
• rs10402601
• NM_172341.4:c.61+17G>C

Variant summary

Our verdict is Benign. The variant received -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:6
• Conservation: PhyloP100: 1.10
• Publications: 21 publications found

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]

PSENEN Gene-Disease associations (from GenCC):

• acne inversa, familial, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Dowling-Degos disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000188223 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 518298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172341.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSENEN	NM_172341.4	MANE Select	c.61+17G>C		intron	N/A	NP_758844.1
	PSENEN	NM_001281532.3		c.61+17G>C		intron	N/A	NP_001268461.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSENEN	ENST00000587708.7	TSL:1 MANE Select	c.61+17G>C		intron	N/A	ENSP00000468411.1
	PSENEN	ENST00000222266.2	TSL:1	c.61+17G>C		intron	N/A	ENSP00000222266.1
	ENSG00000188223	ENST00000591613.2	TSL:2	n.61+17G>C		intron	N/A	ENSP00000468389.2

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

GnomAD2 exomes AF: 0.159 AC: 39857 AN: 250718 AF XY: 0.165

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 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

African (AFR) AF: 0.111 AC: 3709 AN: 33450

American (AMR) AF: 0.180 AC: 8054 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 6428 AN: 26124

East Asian (EAS) AF: 0.0834 AC: 3308 AN: 39682

South Asian (SAS) AF: 0.234 AC: 20202 AN: 86220

European-Finnish (FIN) AF: 0.0758 AC: 4038 AN: 53276

Middle Eastern (MID) AF: 0.236 AC: 1361 AN: 5764

European-Non Finnish (NFE) AF: 0.149 AC: 165023 AN: 1110676

Other (OTH) AF: 0.154 AC: 9288 AN: 60342

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

African (AFR) AF: 0.109 AC: 4516 AN: 41516

American (AMR) AF: 0.174 AC: 2668 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 872 AN: 3472

East Asian (EAS) AF: 0.0888 AC: 460 AN: 5182

South Asian (SAS) AF: 0.245 AC: 1182 AN: 4828

European-Finnish (FIN) AF: 0.0713 AC: 756 AN: 10604

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10485 AN: 67996

Other (OTH) AF: 0.180 AC: 380 AN: 2114

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acne inversa, familial, 2 Benign:4

Jan 15, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 25, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.58
PhyloP100		1.1
PromoterAI		0.077	Neutral
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: rs10402601; hg19: chr19-36236909; COSMIC: COSV53074159; COSMIC: COSV53074159;