rs2293688

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr19-35746344-C-A
• chr19-35746344-C-G
• chr19-35746344-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_172341.4(PSENEN):​c.62-75C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000093 in 1,075,224 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: 9.3e-7 (0 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]

ENSG00000188223 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 9.30e-7 AC: 1 AN: 1075224 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 551900

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000130

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.8
DANN	Benign	0.21

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-36237245;