NM_015331.3:c.191-1405G>C

Variant names:

• chr1-160347594-G-C
• rs2038781
• NM_015331.3:c.191-1405G>C

Variant summary

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

The NM_015331.3(NCSTN):​c.191-1405G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.967 in 152,266 control chromosomes in the GnomAD database, including 71,214 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 0.97 (71214 hom., cov: 31)
• Consequence: NCSTN NM_015331.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0470
• Publications: 1 publications found

Genes affected

NCSTN (HGNC:17091): (nicastrin) This gene encodes a type I transmembrane glycoprotein that is an integral component of the multimeric gamma-secretase complex. The encoded protein cleaves integral membrane proteins, including Notch receptors and beta-amyloid precursor protein, and may be a stabilizing cofactor required for gamma-secretase complex assembly. The cleavage of beta-amyloid precursor protein yields amyloid beta peptide, the main component of the neuritic plaque and the hallmark lesion in the brains of patients with Alzheimer's disease; however, the nature of the encoded protein's role in Alzheimer's disease is not known for certain. Mutations in this gene are associated with familial acne inversa. A pseudogene of this gene is present on chromosome 21. Alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Feb 2014]

NCSTN Gene-Disease associations (from GenCC):

• acne inversa, familial, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.982 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015331.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCSTN	NM_015331.3	MANE Select	c.191-1405G>C		intron	N/A	NP_056146.1	Q92542-1
	NCSTN	NM_001290184.2		c.131-1405G>C		intron	N/A	NP_001277113.1	Q92542-2
	NCSTN	NM_001349729.2		c.191-1405G>C		intron	N/A	NP_001336658.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCSTN	ENST00000294785.10	TSL:1 MANE Select	c.191-1405G>C		intron	N/A	ENSP00000294785.5	Q92542-1
	NCSTN	ENST00000368063.6	TSL:1	n.*120-1405G>C		intron	N/A	ENSP00000357042.2	A0A2U3TZL9
	NCSTN	ENST00000913597.1		c.245-1405G>C		intron	N/A	ENSP00000583656.1

Frequencies

GnomAD3 genomes AF: 0.967 AC: 147104 AN: 152148 Hom.: 71152 Cov.: 31

Gnomad AFR AF: 0.990

Gnomad AMI AF: 0.996

Gnomad AMR AF: 0.979

Gnomad ASJ AF: 0.978

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.952

Gnomad FIN AF: 0.973

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.946

Gnomad OTH AF: 0.973

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

GnomAD4 genome AF: 0.967 AC: 147225 AN: 152266 Hom.: 71214 Cov.: 31 AF XY: 0.969 AC XY: 72116 AN XY: 74456

African (AFR) AF: 0.990 AC: 41127 AN: 41534

American (AMR) AF: 0.979 AC: 14986 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.978 AC: 3396 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5171 AN: 5178

South Asian (SAS) AF: 0.953 AC: 4599 AN: 4828

European-Finnish (FIN) AF: 0.973 AC: 10316 AN: 10602

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.946 AC: 64379 AN: 68030

Other (OTH) AF: 0.973 AC: 2055 AN: 2112

Alfa AF: 0.952 Hom.: 8565

Bravo AF: 0.971

Asia WGS AF: 0.977 AC: 3400 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	8.3
DANN	Benign	0.78
PhyloP100		-0.047
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2038781; hg19: chr1-160317384;