19-35746001-ATCGCTAGGG-A

Variant names:

• chr19-35746001-ATCGCTAGGG-A
• rs2146518798
• NM_172341.4:c.61+13_61+21delGCTAGGGTC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_172341.4(PSENEN):​c.61+13_61+21delGCTAGGGTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSENEN NM_172341.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.66
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 19-35746001-ATCGCTAGGG-A is Benign according to our data. Variant chr19-35746001-ATCGCTAGGG-A is described in ClinVar as [Likely_benign]. Clinvar id is 1566437.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSENEN	NM_172341.4	c.61+13_61+21delGCTAGGGTC		intron_variant	Intron 2 of 3	ENST00000587708.7	NP_758844.1
PSENEN	NM_001281532.3	c.61+13_61+21delGCTAGGGTC		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.61+11_61+19delTCGCTAGGG		intron_variant	Intron 2 of 3	1	NM_172341.4	ENSP00000468411.1
PSENEN	ENST00000222266.2	c.61+11_61+19delTCGCTAGGG		intron_variant	Intron 2 of 3	1		ENSP00000222266.1
ENSG00000188223	ENST00000591613.2	n.61+11_61+19delTCGCTAGGG		intron_variant	Intron 2 of 10	2		ENSP00000468389.2
PSENEN	ENST00000591949.1	c.61+11_61+19delTCGCTAGGG		intron_variant	Intron 2 of 2	2		ENSP00000468593.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 10, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.7

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2146518798; hg19: chr19-36236902;