19-35746344-C-G

Position:

• chr19-35746344-C-G

Variant summary

Our verdict is Benign. Variant got -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

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 -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/exons	MANE	UniProt
PSENEN	NM_172341.4	c.62-75C>G		intron_variant		ENST00000587708.7
PSENEN	NM_001281532.3	c.62-75C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSENEN	ENST00000587708.7	c.62-75C>G		intron_variant		1	NM_172341.4	P1
PSENEN	ENST00000222266.2	c.62-75C>G		intron_variant		1		P1
PSENEN	ENST00000591949.1	c.62-75C>G		intron_variant		2

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

Gnomad4 AFR exome AF: 0.567

Gnomad4 AMR exome AF: 0.348

Gnomad4 ASJ exome AF: 0.341

Gnomad4 EAS exome AF: 0.232

Gnomad4 SAS exome AF: 0.399

Gnomad4 FIN exome AF: 0.352

Gnomad4 NFE exome AF: 0.332

Gnomad4 OTH exome AF: 0.339

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

Gnomad4 AFR AF: 0.559

Gnomad4 AMR AF: 0.351

Gnomad4 ASJ AF: 0.358

Gnomad4 EAS AF: 0.234

Gnomad4 SAS AF: 0.405

Gnomad4 FIN AF: 0.337

Gnomad4 NFE AF: 0.342

Gnomad4 OTH AF: 0.412

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2293688; hg19: chr19-36237245; COSMIC: COSV53076049; COSMIC: COSV53076049;