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

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_172341.4(PSENEN):​c.62-75C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,075,226 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: PSENEN NM_172341.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0880
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSENEN	NM_172341.4	c.62-75C>T		intron_variant	Intron 2 of 3	ENST00000587708.7	NP_758844.1
PSENEN	NM_001281532.3	c.62-75C>T		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>T		intron_variant	Intron 2 of 3	1	NM_172341.4	ENSP00000468411.1
PSENEN	ENST00000222266.2	c.62-75C>T		intron_variant	Intron 2 of 3	1		ENSP00000222266.1
ENSG00000188223	ENST00000591613.2	n.62-75C>T		intron_variant	Intron 2 of 10	2		ENSP00000468389.2
PSENEN	ENST00000591949.1	c.62-75C>T		intron_variant	Intron 2 of 2	2		ENSP00000468593.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000558 AC: 6 AN: 1075226 Hom.: 0 AF XY: 0.00000362 AC XY: 2 AN XY: 551900

African (AFR) AF: 0.00 AC: 0 AN: 25770

American (AMR) AF: 0.00 AC: 0 AN: 43028

Ashkenazi Jewish (ASJ) AF: 0.0000425 AC: 1 AN: 23538

East Asian (EAS) AF: 0.00 AC: 0 AN: 37950

South Asian (SAS) AF: 0.00 AC: 0 AN: 77962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5062

European-Non Finnish (NFE) AF: 0.00000648 AC: 5 AN: 772048

Other (OTH) AF: 0.00 AC: 0 AN: 47884

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.5
DANN	Benign	0.93
PhyloP100		0.088

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;