NM_172341.4:c.62-75C>G

Variant names:

• chr19-35746344-C-G
• rs2293688
• NM_172341.4:c.62-75C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_172341.4(PSENEN):​c.62-75C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 1,225,486 control chromosomes in the GnomAD database, including 77,644 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.40 (12942 hom., cov: 31)
  • Exomes 𝑓: 0.34 (64702 hom.)
• Consequence: PSENEN NM_172341.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0880
• Publications: 13 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSENEN	NM_172341.4	c.62-75C>G		intron_variant	Intron 2 of 3	ENST00000587708.7	NP_758844.1
PSENEN	NM_001281532.3	c.62-75C>G		intron_variant	Intron 2 of 3		NP_001268461.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSENEN	ENST00000587708.7	c.62-75C>G		intron_variant	Intron 2 of 3	1	NM_172341.4	ENSP00000468411.1
PSENEN	ENST00000222266.2	c.62-75C>G		intron_variant	Intron 2 of 3	1		ENSP00000222266.1
ENSG00000188223	ENST00000591613.2	n.62-75C>G		intron_variant	Intron 2 of 10	2		ENSP00000468389.2
PSENEN	ENST00000591949.1	c.62-75C>G		intron_variant	Intron 2 of 2	2		ENSP00000468593.1

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60842 AN: 151778 Hom.: 12924 Cov.: 31

Gnomad AFR AF: 0.559

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.403

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.409

GnomAD4 exome AF: 0.341 AC: 366120 AN: 1073590 Hom.: 64702 AF XY: 0.343 AC XY: 188911 AN XY: 551128

African (AFR) AF: 0.567 AC: 14594 AN: 25738

American (AMR) AF: 0.348 AC: 14947 AN: 43010

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 8020 AN: 23534

East Asian (EAS) AF: 0.232 AC: 8813 AN: 37948

South Asian (SAS) AF: 0.399 AC: 31093 AN: 77920

European-Finnish (FIN) AF: 0.352 AC: 14782 AN: 41976

Middle Eastern (MID) AF: 0.358 AC: 1807 AN: 5054

European-Non Finnish (NFE) AF: 0.332 AC: 255851 AN: 770600

Other (OTH) AF: 0.339 AC: 16213 AN: 47810

GnomAD4 genome AF: 0.401 AC: 60914 AN: 151896 Hom.: 12942 Cov.: 31 AF XY: 0.399 AC XY: 29585 AN XY: 74220

African (AFR) AF: 0.559 AC: 23140 AN: 41410

American (AMR) AF: 0.351 AC: 5362 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 1241 AN: 3466

East Asian (EAS) AF: 0.234 AC: 1208 AN: 5158

South Asian (SAS) AF: 0.405 AC: 1948 AN: 4812

European-Finnish (FIN) AF: 0.337 AC: 3547 AN: 10538

Middle Eastern (MID) AF: 0.370 AC: 108 AN: 292

European-Non Finnish (NFE) AF: 0.342 AC: 23213 AN: 67936

Other (OTH) AF: 0.412 AC: 869 AN: 2110

Alfa AF: 0.383 Hom.: 1452

Bravo AF: 0.405

Asia WGS AF: 0.359 AC: 1249 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.7
DANN	Benign	0.52
PhyloP100		0.088
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs2293688; hg19: chr19-36237245; COSMIC: COSV53076049; COSMIC: COSV53076049;